CZ20002269A3 - Integrin receptor antagonizing substances - Google Patents

Abstract

The present invention relates to substances capable of antagonizing the integrin receptors. These substances can also be used in the form of a pharmaceutical composition which also forms part of the solution for the treatment of various diseases mediated by said receptors, such as bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, artherosclerosis, inflammation, insufficient wound healing, viral diseases and tumor growth and metastasis.

Description

Integrin receptor antagonists

Technical field

The present invention relates to integrin receptor antagonists. They are suitable for use in inhibiting bone resorption, treating and preventing osteoporosis, diabetic retinopathy, viral diseases and tumor growth including metastasis.

Dosavadn? state of the art

It is believed that a variety of disease states can be caused by the action of integrin receptors, so that agents that antagonize these receptors represent a very useful class of active agents. Integrin receptors are heterodimeric transmembrane proteins by which cells connect and communicate with the extracellular matrix and other cells according to S. B. Rodan and G. A. Rodan,

Integrin Function In Osteoclasts, Journal of Endocrinology, Volume 154, pp. 47-56, 1997.

Bone tissue resorption is mediated by the action of cells called osteoclasts. Osteoclasts are large multinuclear cells with a diameter of 400 nm that resorb mineralized tissues, predominantly calcium carbonate and phosphate carbonate in vertebrates. Osteoclasts are actively motile cells that migrate across the bone surface, can bind to bone tissues and secrete the necessary acids and proteases to resorb mineralized bone tissue. Osteoclasts appear to exist in at least two physiological states, a secretory state and a movable state. In the secretory state, these are flat cells that adhere to the bone matrix via the junction region, are highly polarized, form a roughened boundary, and secrete lysosomal enzymes and protons for bone resorption. Adhesion of osteoclasts to the bone surface is important

the initial degree of bone resorption. In a moving or migratory state, osteoclasts migrate along the bone matrix and do not participate in resorption until they reconnect to bone tissue.

Integrins are involved in the adhesion of the osteoclast to the bone surface and in their activation and migration. The most widespread integrin in osteoclase, eg in rats, chickens, mice and humans, is the integrin receptor, referred to as ανβ3, which receptor appears to interact in bone with matrix proteins that contain the RGD sequence. Antibodies against ανβ3 block bone resorption in vitro, demonstrating that this integrin plays a key role in resorption. There is increasing evidence that ανβ3-binding agents can be used effectively to inhibit bone resorption induced by osteoclasts in vivo in mammals.

The most widespread bone disease is currently osteoporosis, followed by hypercalcaemia in malignant tumors, osteopenia in bone metastases, osteoporosis, increased thyroid activity, periarticular erosion in rheumatoid arthritis, Paget's disease, osteopenia, induced immobility and osteopormosis, osteoporosis. All of these conditions are characterized by a decrease in bone tissue caused by an imbalance between bone resorption and formation, this process continuing throughout life at an average rate of approximately 14% per year. However, the rate of bone exchange varies at different sites. It is higher in the vertebral bone of the vertebrae and jaws than in the compact tissue of long bones. The potential loss of bone tissue is directly proportional to that tissue exchange and may amount to more than 5% per year in vertebrae immediately after menopause, leading to an increased risk of fracture.

There are approximately 20 million people in the United States with demonstrable vertebral fractures due to osteoporosis. Moreover • ·

approximately 250,000 femoral neck fractures per year due to osteoporosis. This clinical situation is associated with% mortality 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 α 1β 5 integrin 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 for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis.

·· ·· ··· ··· ·· ··

In addition, the compounds of the present invention may inhibit angiogenesis and inflammatory conditions by antagonizing the α 1βδ integrin receptor expressed in 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 Balls 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 also participates in inflammation in epithelial cells and arises in response to local injury or inflammation according to Xiao-Zhu Huang et al. 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 ανβδ receptors. These substances, referred to 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 compounds of the invention may antagonize α1β3, ανβ5 and ανβδ 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 class of α 1β receptor antagonists.

Moreover, it is 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 compounds having a dual antagonistic effect on α 1β 3 / α 1βδ receptors.

It is also an object of the present invention to provide a class of substances having an inhibitory effect on α1β3, ανβδ and ανβδ receptors.

The present invention is also directed to 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 • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · ·

from groups

x-Υ — N • · · ·

• · · · v v v v v v v v

R ⁷ R ⁸

Ν 'i

N

CO ₂ R ^p

wherein the dotted line a represents a single or double bond, provided that when a represents a double bond, the carbon atoms from which the double bond is derived can only be substituted by R ¹⁰ and R ¹² ,

X is selected from groups

NR ² - C-NR ¹ R ² NR ³ - 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 the group N, O and S, wherein the ring nitrogen atoms are unsubstituted or substituted with one substituent R ¹ and the ring carbon atoms are unsubstituted or substituted with one or two substituents R ¹ or a 9- to 14-membered polycyclic ring system in which one or more the number of rings is aromatic, the polycyclic ring system containing 0, 1, 2, 3 or 4 N, O and S heteroatoms, the ring nitrogen atoms being unsubstituted or substituted by one substituent R ¹ and the ring carbon atoms being unsubstituted or are substituted with one or two substituents R ¹ ,

Y is selected from groups

- _(CH2) nR, <CH2) m O- (CH2) n-,

- (CH ₂ ) m -NO ⁴ - (CH 2) n -,

- (CH2) nrS- (CH _{2) n} -

- (CH 2) n x -SO- (CH ₂ ) n -

- (CH 2) m -SO _{2 -} (CH ₂ ) n -,

- (CH ₂₎ m O- (CH ₂₎ io (CH 2} _p)

- (CH ₂₎ m O- (CH2) n-KR4- (CH 2) p

- (CH2) m-KR4- _(CH2) n-NK 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 -N 4 - (CH 2) n -O- (CH ₂ ) p

- (CH 2) _m -S- (CH 2) n O- (CH ₂ ) p

TCH _{2) m} -S- (CH2) n-NK4- (CH2) pa

- (CH ₂ ) m -Z- (CH 2) n -, wherein Z represents a 3- to 10-membered monocyclic or polycyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, the ring nitrogen atoms are unsubstituted or substituted by one substituent R ¹ and the ring carbon atoms are unsubstituted or substituted by one or two substituents R ¹ , in addition, any carbon atom of the methylene group CH 2 in the meaning of Y may be different from R ⁴ , substituted with one or two 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, C1-3 acylamino,

C1-3acylaminoC1-8alkyl, (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, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C 1-8 alkyl-S (O) _p , (C 1-8 alkyl) _p aminocarbonyl, C 1-8 alkyloxycarbonylamino 8 alkyl) _p aminocarbonyloxy, (arylC1-8alkyl) _p amino, (aryl) _p amino, and arylC1-8alkylsulfonylaminoskupina C1-8alkylsulfonylaminoskupina or form two R ¹ on the same aluminum atom, together with that 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,

C1-8alkylcarbonylamino, arylC1-5-alkoxy,

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

C 1-6 alkylcarbonyloxy,

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

HCz C- (CH ₂ ) t -,

C 1-6 alkyl-C = C- (CH ₂ ) t -,

C 3-7 cycloalkyl-C = C- _(CH2) t-, aryl-C5C - (. _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 -,

C1-6alkylaryl-CH = CH- (CH ₂₎ r,

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

C1-8-alkylsulfonylamino, C1-4 alkylsulfonylamino, C1-4 alkylsulfonylamino, C1-4 alkylsulfonylamino, C1-4 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 aminosulfonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminosulfonylamino, (arylC1-8alkyl) _p aminosulfonylaminoC1-6alkyl,

C1-6alkylsulfonyl,

C 1-6 alkylsulfonylC 1-6 alkyl, arylsulfonylC 1-6 alkyl, aryl IC 1-6 alkyl Isonium, arylC 1-6 alkylsulfonylC 1-6 alkyl,, · ♦ ♦ ♦ « · * * • φ · φ · ·· * <

«♦ · φ« · φ φ φ φ

9 9 · 99 99 99 99

C 1 -C 6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, and IC1-6alkyl I and IC1-6alkyl I,

C 1-6 alkylthiocarbonylamino,

C1-6alkylthiokarbonylaminoC1-6alkyl, arylthiokarbonylaminoC1-6alkyl, arylC 1-6alkylthiokarbonylaminoskupina, arylC1-6alkylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC1-8alkyl) _p aminocarbonyl, (aryl 1 -8alkyl) _β aminocarbonylC 1-6 alkyl, or form two R ³ substituents on the same carbon atom together with the carbonyl or cyclopropyl group, wherein any R ³ alkyl group is unsubstituted or substituted by 1 to 3 R ¹ substituents, provided that: that R ³ is selected such that in the resulting compound the carbon atom (s) to which R ³ is attached is attached 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,

C1-8alkyl, arylC1-6alkyl, * 9 ♦♦♦ «* ♦ 99 ·· ·· ·» · 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

99,999,999 99. 9 (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,

C1-8alkylaminosulfonyl, (aryl) _p- aminosulfonyl, (arylC1-8alkyl) _p- aminosulfonyl, arylsulfonyl, arylC1-6alkylsulfonyl,

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,

C1-10 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) 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, • ···· * 9 · 4

· 4

9 «··

999 ··· ·· · 9 · 9 · 4 · 4 4 4 · 4 4 4 · · · 4 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, 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 -,

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 ) _t -,

C 1-6 alkylaryl-SO ₂ (CH ₂ ) _t -,

C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl,

0000 00 00

0 · 0 0 0

0 0 0 0> 0 0 0 0 0 0 0 0 0

000 00 00 (aryl) _p amino, (aryl) _p aminoC1-6alkyl (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _p aminoC1-6alkyl, arylcarbonyloxy, arylC1-6alkylkarbonyloxyskupina, (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,

4444 • 4 44 • 44

4 4 »44 • 4 44

4 4 4 4 4

4 4 4 4

4 4 4 4 4

444 · 44 44 44 (aryl) _p aminosulfonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminosulfonylamino, (arylC1-8alkyl) _p aminosulfonylaminoC1-6alkyl,

C 1-6 alkylsulfonyl,

C 1-6 alkylsulfonylC 1-6 alkyl, aryl of Ifon IC 1 -Galkyl, 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,

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

R ⁷ and R ⁸ are independently selected from hydrogen, aryl, «« * ♦ ·· · »· ·· • * · · · · ·· · * * ♦ • ·« · · · · * «♦ '· ♦ · · · · · · ·

C 1-10 alkyl, aryl- (CH ₂ ) _r -O- (CH ₂ ) _s -, aryl- (CH ₂ ) _r S (O) _p - (GH ₂ ) _s -, aryl- (CH ₂ ) _r -C (O) - _(CH2) s-, aryl- _{(CH2) 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, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6 and alkyl,

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} -,

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- (CH _{2) y} • ·· · *

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) _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, 4 · 4 · 4 ·· 444 *

(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 aminosulfonylamino, (arylC 1-8alkyl) _p aminosulfonylaminoC1-6alkyl, C1-6alkylsulfonyl,

C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkylsulfonyl, ary IC1-6alkyl Isu IfonylC1-6alkyl,

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 aminocarbonylC1-6alkyl (8alkyl) _β aminocarbonylC 1-6 alkyl,

C7-20polycyclylC0-8alkylsulfonylamino, • 9 99 9

9 9

9 9

9 9 9 ·· 99

99,999 9

9

9 9 9 9 9

9

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 chosen 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, arylC 1-8 alkyl,

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

C 1-8 alkylaminocarbonylmethylene,

C1-8dialkylaminocarbonylmethylene,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen,

C 1-8 alkyl, aryl, halogen, hydroxy, aminocarbonyl,

C3-8cycloalkyl, aminoC1-6alkyl, (aryl) _p aminocarbonyl, hydroxycarbonyl, (arylC1-5alkyl) _p aminocarbonyl, hydroxycarbonylC1-6 alkyl, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (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,

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

C 1-6 alkylthiocarbonyl, arylthiocarbonyl, arylC 1-6 alkylthiocarbonyl, 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- ( _{CH2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH ₂₎ r -N (R ⁴⁾ - (CH _{2) s} -,

HCz C- (CH ₂ ) _t -,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C5C- (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 -,

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

C 1-6 alkylaryl-CH = CH- (CH ₂ ) t -, i

• 9 9 * 9 »9 99 • • 9 9 9 99 9 9 9 9 • » • 9 9 9 9 « ·· • 9 · * 9 999 99 9 9 9 99 9 9 9 9

C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -,

C1 -6alkylaryl -SO ₂ (CH _{2) r,}

C1-8alkylcarbonylamino, arylC1-5alkoxy,

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

C1-6alkylcarbonyloxy, (C1-6alkyl) _p amino, aminocarbonylC1-6alkyl,

C1-6alkoxy, arylC1-6alkoxy, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _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,

C 1-8 alkylcarbonylaminoC 1-6 alkyl, arylcarbonylaminoC 1-6 alkyl,

• • »· • • • 999 9 ·· ·· 99 99 • 9 9 9 • · • • • · • • 9 · « 99 ··· • 9 9 99 9 9

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 aminocarbonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) ) _p amiriosulfonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminosulfonylamino, (arylC1-8alkyl) _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,

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 1-6 alkyl) _p aminocarbonyl

499 ···· 9 · 9

9 9

9 9 9

4 9 9

49 9

99

4 9 4 4

4 4 4 4

9 9 4

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

R ¹⁰ and R ¹² together with the carbon atom to which they are attached form a 5 to ¹² carbon atom

7-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 substituent R ¹ and the ring carbon atoms are unsubstituted or are substituted with one or two substituents R ¹ , and furthermore any alkyl group R ¹⁰ , R ¹¹ , R ¹² and R ^{13 is} unsubstituted or substituted with 1 to 3 substituents R ¹ , 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, v independently represents an integer from 0 to 3 2, 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.

Accordingly, the present invention relates to integrin receptor antagonists.

The compounds can be represented by formulas

OR ⁷ R ^a

X-Y "

co ₂ r ⁹ o R ⁷ R ⁸

CO ₂ R ⁹ wherein the dashed line a represents a single or double bond, provided that when a represents a double bond, the carbon atoms from which the double bond is derived can only be substituted by R ¹⁰ and R ¹² ,

X is selected from groups

II - C-NR ¹ R ²

NR ²

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

Y is selected from groups

- (CH 2) m ->

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

- (CH 2) _m -KR <(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 N ⁴ - ⁴ - ( ^CH 2) p;

- (CH 2) m-NK ⁴ - (CH 2) n N ⁴ - (C 2 ^H ) p -,

- (CH2) m-O '(CH2) n-S- (CH2) p

- (CH2) S- (CH2) ns (CH2) p - (CH _{2) m} -KR4- (CH2) ns (CH ₂₎ p - (CH ₂₎ m ^KR4 - <CH2) n O- (CH2 ) - (CH2) m-S- (CH2) nO- (CH2) p - (CH2) mS- (CH2) n-NB. ^4- (CH 2) p - (CH 2) m - · Ζ- (CH 2) n -, wherein Z represents a 3- to 10-membered monocyclic or polycyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from N, O and S, the nitrogen atoms in the ring are unsubstituted or substituted with one R ¹ substituent and the ring carbon atoms are unsubstituted or substituted with one or two substituents R ¹ and besides can be any carbon atom of the methylene group CH ₂ in the meaning of Y, other than R ⁴ , substituted with one or two 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, C1-3 acylamino, Ti-Ti;

C1-3acylaminoC1-8alkyl, (C1-6alkyl) _p amino, (C1-6alkyl) _p aminoC1-8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-3alkoxycarbonyl, C1-3alkoxycarbonylC1-6alkyl, hydroxycarbonylC 1-6 alkyloxy, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C 1-8 alkyl-S (O) _p , (C 1-8 alkyl) _p aminocarbonyl, C 1-8 alkyloxy -8alkyl) _p aminocarbonyloxy, (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 aluminum 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 - (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,

C1-8alkylcarbonylamino, arylC1-5-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 -,

3-7-CH = CH- (CH _{2) t} -, aryl-CH = CH- _(CH2) 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} -, C 1-6 alkoxy, arylC 6 alkoxy, arylC -6alkyl, (C1-6alkyl) aminoC1-6alkyl _P, (aryl) _p amino, (aryl) _p aminoC1-6alkyl ( arylC1-6alkyl) _p amino, (arylC1-6alkyl) _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 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 aminosulfonylaminoC1-6alkyl, (arylC 1-8alkyl) _p aminosulfonylamino, (arylC1-8alkyl) _p aminosulfonylaminoC1-6alkyl,

C 1-6 alkylsulfonyl,

C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkylsulfonyl, arylC1-6alkylsulfonylC1-6alkyl, »4 9 4 4 4

4 4 4

4 4 4 4 4 9 4 4 5

4 4 4 44 9 4

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 _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, hydroxycarbonylC1-6alkyl,

C 1-8 alkyl, arylC 1-6 alkyl,

0 · 0 0 0 0 0 0 0 ··· ·· ·· «00« 0 00 (C1-6alkyl) aminoC2-6alkyl _p (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,

C1-8alkylaminosulfonyl, (aryl) _p- aminosulfonyl, (arylC1-8alkyl) _p- aminosulfonyl, arylsulfonyl, arylC1-6alkylsulfonyl,

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

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

C1 -1 Oalkyl, aryl- (CH _{2) r} -O ~ _{(CH2) 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, • • 9 · · · · · · · • ·· 9, -, 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, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) _t -,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C3-7cycloalkyl-C5C- _(CH2) t-, aryl-C = C ~ _{(CH2) t} -,

C 1-6 alkylaryl-C = C- (CH ₂ ) _t -,

CH ₂ = CH- (CH _{2) r,}

C 1-6 alkyl-CH = CH- (CH ₂ ) _t -,

3-7-CH = CH- (CH _{2) 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, 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, • · 9 · 9 9 • 9 (aryl) _p aminosulfonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminosulfonylamino, (arylC1-8alkyl) _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,

C1-6alkyithiokarbonylaminoC1-6alkyl, arylthiokarbonylaminoC1-6alkyl, arylC 1-6alkylthiokarbonylaminoskupina, arylC1-6a! KylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC -8alkyl) _p aminocarbonyl, ( aryl ( _C 1-8 alkyl) _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 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 the group consisting of hydrogen, aryl;

4 4 4

4 4 4 ·· 44

C1-10 alkyl, 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 (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, 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- (GH ₂₎ t-

C 1-6 alkylaryl-C = C- (CH ₂ ) _t -,

CH ₂ = CH- (CH _{2) r,}

C 1-6 alkyl-CH = CH- (CH ₂ ) _t -,

3-7-CH = CH- (CH ₂₎ t • 0

0 0 0

0 0 0

0 0 0 ·· 00 aryl-CH = CH- (CH ₂ ) t -,

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

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, 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,

99

9 9 9

9 9 9

9 9 9

9 9 9

99 9 9 9 9 9 9 9 9

999 999 (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl, (aryl) _p aminocarbonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8 alkyl) _p aminosulfonylaminoskupina, (C1-8 alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) _p aminosulfonylaminoC1-6alkyl (arylC -8alkyl) _p aminosulfonylaminoskupina (arylC C8alkyl) _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,

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 8alkyl) _p aminocarbonylC1-6alkyl, C7-20polycyclylC0-8alkylsulfonylamino, · • φ φφφ I I I I I I I I I I I I I I I

wherein any of the R ⁷ and R ⁸ alkyl groups is unsubstituted or substituted with 1 to 3 R ¹ substituents, provided that R ⁷ and R ⁸ are selected such that the resulting compound has a carbon atom on which the symbols are indicated bound, bound by at most one heteroatom,

R ⁹ is selected from hydrogen

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

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

C 1-8 alkylaminocarbonylmethylene,

C1-8dialkylaminocarbonylmethylene,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen,

C 1-8 alkyl, aryl, halogen, hydroxy, aminocarbonyl,

C3-8cycloalkyl, aminoC1-6alkyl, (aryl) _p aminocarbonyl, hydroxycarbonyl, (arylC1-5alkyl) _p aminocarbonyl, hydroxycarbonylC1-6alkyl, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p aminoC2 -6alkyl,

C 1-8 alkylsulfonyl,

C 1-8 alkoxycarbonyl, aryloxycarbonyl, 9 · 4 »4

4 4 4 4 4 4

4 4 · 4

44 444 • «3 ··

4 4 4 ·

4 4 * 4

4 4 · 4 ·

4 4 4 4 »·· 4 4 44 ary IC 1-8alkoxy carboys I,

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,

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

C 1-6 alkylthiocarbonyl, arylthiocarbonyl, arylC 1-6 alkylthiocarbonyl, 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} -,

HCz 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 = C- (CH ₂ ) _t -,

CH ₂ = CH- (CH ₂ ) t -,

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

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

C 1-6 alkylaryl-CH = CH- (CH ₂ ) t -,> 9 · * 9 • ·

9 · 9

I 9 9 4

I 9 9 «

I 9 9 1 9 9 4 9 99

C 1-6 alkyl-SO ₂ - (CH ₂ ) t -,

C 1-6 alkylaryl-SO ₂ (CH ₂ ) _t -,

C1-8alkylcarbonylamino, arylC1-5alkoxy,

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

C1-6alkylcarbonyloxy, (C1-6alkyl) _p amino, aminocarbonylC1-6alkyl,

C1-6alkoxy, arylC1-6alkoxy, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _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,

C 1-8 alkylcarbonylaminoC 1-6 alkyl, arylcarbonylaminoC 1-6 alkyl, C 9-6 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 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 (arylC -8alkyl) _p aminosulfonylaminoC1-6alkyl C1 -6alkylsulfonyl,

C 1-6 alkylsulfonylC 1-6 alkyl, arylsulfonylC 1-6 alkyl, arylC 1-6 alkylsulfonyl I, arylC 1-6 alkylsulfonylC 1-6 alkyl,

C 1-6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6aalkyl, 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 1-6 alkyl) _p aminocarbonyl 4 4444 • · ·

4 ·

4 4

4 4 4

4 44 »4

4 •

• 44 4

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

R ¹⁰ and R ¹² together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from N, O and S, the nitrogen atoms in the ring, they are unsubstituted or substituted by one substituent R ¹ and the ring carbon atoms are unsubstituted or are substituted by one or two substituents R ¹ , and in addition any alkyl group R ¹⁰ , R ¹¹ , R ¹² and R ^{13 is} unsubstituted or substituted 1 to 3 substituents R ^1, m independently represents an integer of 0-6, n is independently an integer from 0 to 6, p is independently an integer from 0 to 2, r is independently an integer 1-3, p is independently an integer from 0 to 3, t independently represents an integer from 0 to 3, v independently represents an integer from 0 to 2, as well as pharmacologically acceptable salts thereof.

In one embodiment, the invention relates to compounds of structural formulas

and.

wherein the dotted line represents a single or double bond, provided that in the case of a double bond, the carbon atoms from which the bond is derived are substituted only by R ¹⁰ and R ¹² .

A group of compounds of this embodiment can be represented by a structural formula

wherein the dashed line a represents a single or double bond, provided that when the double bond is a carbon atom,

of which the linkage originates, substituted only with R and R ^12th

In a subgroup of this class of compounds, the active compounds can be represented by the structural formula.

R

• R

R ¹¹ R ¹² • o χ

X Υ — Ν Ν— (0 H2y _v

In the compounds of the invention, X is preferably a 6-membered monocyclic aromatic ring system containing one or two 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 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 and the carbon atoms in the ring are unsubstituted or substituted by 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 groups

- (CH ₂ ) _m -,

- (CH ₂ ) _m -O- (CH ₂ ) n ',

- (CH 2) _m -NR 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 -NR 4 - (CH 2) p -,

- (CH 2) m -NR ⁴ - (CH 2) n -NNE (CH 2) p -, a

- (CH 2) m -NR N (CH 2) n O- (CH 2) p -, wherein any carbon atom in the methylene group CH ₂ in the meaning of Y, other than R ⁴ , is optionally substituted with 1 or 2 substituents R ³ .

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

A particularly preferred value for Y is (CH ₂ ) _m or (CH ₂ ) _m -NR ⁴ - (CH ₂ ) n,

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.

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 38 cycloheteroalkyl, hydroxy, nitro, cyano, trifluoromethyl and trifluoromethoxy.

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

O

In the compounds of the invention, R is preferably one of 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, arylC 1-6 alkyl, i

• 9 • 9 • 9 • 9

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,

C1-6alkylsulfonyl, arylsulfonyl, arylC1-6alkylsulfonyl, arylC1-6alkylcarbonyl,

C1-8alkylaminocarbonyl, arylC1-5alkylaminocarbonyl, arylC1-8alkoxycarbonyl 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.

In one embodiment of the invention, R ⁵ and R ^{6 are} independently selected from the group consisting of:

hydrogen, aryl,

C1-8alkyl, aryl-C = C- _(CH2) t-, arylC -6alkyl, CH ₂ = CH- (CH _{2) t} -, and HC? C- (CH _{2) t} -.

In a subset of this embodiment, R ⁶ is hydrogen and R ⁵ is selected from hydrogen, aryl,

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

_CH2 = CH- _(CH2) 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,

C1-8alkyl, aryl-C5C- (CH _{2) n} arylC -6alkyl,

CH ₂ = CH- (CH _{2) t} -, and

HC = C- (CH ₂ ) _t -.

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

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, (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 (arylC -8alkyl) _p aminosulfonylaminoC1-6alkyl, C1-6alkylthiokarbonylaminoskupina,

C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl.

In a class of this embodiment, R ⁸ is 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 -8alkoxykarbonylaminoskupina arylC -8alkoxykarbonylaminoskupina, arylaminocarbonylamino, (C1-8 alkyl) _p aminocarbonylamino, (arylC 8 alkyl) _p aminocarbonylamino, (C1-8 alkyl) _p aminosulfonylaminoskupina and (arylC C8alkyl) _p aminosulfonylaminoskupina.

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

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

C1-8alkylsulfonylamino, arylC1-6alkylsulfonylamino,

arylsulfonylamino,

C1-8alkoxykarbonylaminoskupina arylC -8alkoxykarbonylaminoskupina, arylaminocarbonylamino, (C1-8 alkyl) _p aminocarbonylamino, (arylC 8 alkyl) _p aminocarbonylamino, (C1-8 alkyl) _p aminosulfonylaminoskupina and (arylC C8alkyl) _p aminosulfonylaminoskupina.

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, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are preferably independently selected from hydrogen, aryl, C 1-6 alkyl and arylC 1-6 alkyl.

In the compounds of the invention, m is preferably an integer of 0 to 4 and in particular 0 to 3.

In the compounds of the invention, n is preferably an integer from 0 to 4 and in particular from 0 to 3.

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

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

In the compounds of the invention, t is preferably an integer of up to 2 and in particular of 0 to 1.

In the compounds of the invention, preferably v = 0.

In some embodiments of the invention, the compounds of the invention correspond to the formulas having the following indicated stereochemistry at the carbon atom to which R ⁵ and R ⁶ are attached.

R ¹¹

wherein each symbol has the meaning given above.

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

9 9 9 · 9 3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydro-benzofuran-6-yl) -3- (2-oxo-3) - [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (2,3-dihydro-benzofuran- 6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - Propionic acid 3 (S) - (3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl 3-R (3) - (3-Fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]] -imidazolidin-1-yl} -propionic acid 3 (3-Fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) -pyridyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (quinolin-3-yl) -3- {2-oxo-3- [3- ( 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (quinolin-3-yl) -3- {2 -oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] n Afthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8) 3 (S) - (Ethinyl) -3- {2-oxo-3- [3- (2-oxo-3- [2-oxo-3- (2-methylpyridine-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid; 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (ethynyl) -3- {2-oxo -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid,

* · • • 9 • 9999 • 9 9 9 9 9 9 9 • 9 9 9 9 9 9 9 • 9 9 • • • · 9 9 9 9 • · • · • • 9 9 9 9 9 9 99

3- (Ethinyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3-S (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)} -propionic acid -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (pyridin-3-yl) -3- {2-oxo-3- [3- (5, 6,7,8-tetrahydro- [1,8] afthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (Pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -propionic acid 3 (R) - (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine-1- yl} -propionic acid 3 (R) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl-propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-ethoxypyridin-3-yl) -3- {2 -oxo-3- [3- (5,6,7,8-tetrahydro56,4,4,4,4,4,4,4,4,4,4,444 4444 «4» 4,444,444

4444 4 4444 · 4444 · 44 44 4 *

- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolin-1-yl} -propionic acid 3- (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-Methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl3 -imidazolidin-1-yl} -propionic acid 3 (R) - (4-methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [ 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (4-methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5 3 (S) - (6-Amino-pyridin-3-yl) -3,6,6,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) N- (6-aminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - imidazolidin-1-yl} propiones 3- (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -acetic acid -imidazolidin-1-yl} -propionic acid 3- (S) - (4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- { 2-Oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (R) - (4-Methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] • 4,444 • 4 · 4 ·· 4

4 4 4

4 «·

444 ·

44 • 4 * 4

4 4 · 4 ·

4 4 *

44

3- (4-Methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- (2-oxo-3) -imidazolidin-1-yl} -propionic acid - [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazoidin-1-yl} -propionic acid 3 (S) - (6-methylaminopyridinic acid) -3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (6-methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2-fluoro-biphenyl-4-yl) -3- (2-oxo-3) - [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-fluorobiphenyl- 4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - propionic acid, 3- (3-fluorobiphenyl-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl-imidazolidin-1-yl} -p ropionic acid 3 (S) - (2-oxo-2,3-dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1, 5,6,7,8-tetrahydro- 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-oxo-2,3-dihydrobenzoxazol-6-yl) -3- (2-oxo-) 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2-oxo-2, 3-Dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -propionic acid 3 (S) - (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] Naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5, 2-oxo-3-fluorophenyl)] 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (4-ethoxy-3-fluorophenyl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5 -ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1- yl} -propionic acid 3 (R 1- (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - imidazolidin-1-yl} -propionic acid, 3- (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5, 5-hydroxy-pyridin-3-yl) -propionic acid] 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (5-hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (5 -hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1- yl} -propionic acid 2 (S) -benzenesulfonylamino-3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid,

3 (S) - {2-Oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent 4-enoic acid 3 (R) - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -pent-4-enoic acid 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine 1-yl} -pent-4-enoic acid 3 (S) - (5-ethoxy-pyridin-3-yl) -3- (3- {3- [6- (4-methoxy-benzylamino) -pyridin-2-yl) 3-R - (5-ethoxy-pyridin-3-yl) -3- (3- {3- [6- (4-methoxy-benzylamino) -propyl} -2-oxo-imidazolidin-1-yl) -propionic acid -pyridin-2-yl] -propyl} -2-oxo-imidazolidin-1-yl) -propionic acid 3- (5-ethoxypyridin-3-yl) -3- (3- {3- [6- (4) -methoxybenzylamino) -pyridin-2-yl] -propyl} -2-oxo-imidazolidin-1-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2 oxo-imidazolidin-1-yl} -3 (S) - (5-ethoxy-pyridin-3-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2 -oxo-imidazolidin-1-yl} -3 (R) - (5-ethoxy-pyridin-3-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2 -oxo-i Midazolidin-1-yl} -3- (5-ethoxypyridin-3-yl) -propionic acid 3 (S) - (2-oxo-2,3-dihydro-1H-oxa-1,5-diazanaphthalene-7) -yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine 60

-1-yl} -propionic acid 3 (R) - (2-oxo-2,3-dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2-oxo-2,3) -dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-one) -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2, 3-Dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine- 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2,3-dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3- oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3-oxo-3,4- dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- { 2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine

-1-yl} -propionic acid 3 (S) - (3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3,4-dihydro-2H- 1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} -propionic acid 3- (3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3] - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (furo [2,3-b] pyridine- 6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - propionic acid, 3 (S) - (furo [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1, 2-oxo] - [1,2,3] 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (furo [2,3-b] pyridin-6-yl) -3- (2-oxo-) 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3) Dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridium) n-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrofuro [2,3-b] pyridin-6-yl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2,3- Dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,862)

3-S (furo [3,2-b] pyridin-6-yl) -3-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-dihydrofuro [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3-R - (2,3-dihydrofuro [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8)} -propionic acid -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2,3-dihydrofuro [3,2-b] pyridin-6-yl) - 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 ( S) - (Benzimidazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1, 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (benzimidazol-2-yl) -3- {2-oxo-3- [3- (5, 7-oxo-2-yl) -propionic acid] 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (benzimidazol-2-yl) -3- (2-oxo-) 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (1H-imidazo) [4,5-c] pyridin-2-yl) -3- {2-oxo-3- [3- (5,6,7,8) •

3-R - (1H-Imidazo [4,5-c] pyridin-2-yl) -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 - (1H-imidazo [4,5-c] pyridin-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-one)] -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8) 3-R - (Benzoxazol-2-yl) -3- (2-oxo-3-) -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (benzoxazol-2-yl) -3 - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S 1- (1-methyl-1H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)] - 3-R - (1-Methyl-1H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5,6) -propyl] -imidazolidin-1-yl} -propionic acid 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine -1-yl} -propionic acid 3- (1-methyl-1H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [ 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, and pharmaceutically acceptable salts thereof.

Another example of the compounds of the invention may be those of the following group:

3 (S) - (2,3-Dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-) yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3-fluorophenyl) -3- (2-oxo-) 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3-fluorophenyl) ) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (Quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1, 5,6,7,8-tetrahydro- 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (ethynyl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (ethynyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) _: (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1, 5,6,7,8-tetrahydro-] 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (pyridin-3-yl) -3- {2-oxo-3- [3- (5, 7-propyl-2-oxo-3-yl) -propionic acid] 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (pyridin-3-yl) -3- {2 - oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -4-methyl-imidazolidin-1-yl} -propionic acid,

3 (R) - (Pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - 4-Methyl-imidazolidin-1-yl} -propionic acid 3 (S) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-methoxypyridin-3-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6- ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3-R - (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine-)} -propionic acid 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6, 2-yl) -propyl] -imidazolidin-1-yl} 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (4-methoxyquinolin-7-yl) -3- {2 -oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - ( 6-aminopyridin-3-yl) -3- {2-oxo-3- [3- (5, 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-aminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-Methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl-propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (4-methyl-3-oxo-3,4-dihydro-2H) -benzo [1,4] oxazin-7-yl) 66

4 · 4 4

4 4 4

-3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-Methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl 3-R - (6-Methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro-) -imidazolidin-1-yl} -propionic acid [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2-fluorobiphenyl-4-yl) -3- {2-oxo-3- [ 3- (5,6,7,8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-fluorobiphenyl-4- yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -propionic acid, 3 (S) - (2-Oxo-2,3-dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-oxo-2,3-dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-ethoxy-3) -fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8); 3 (R) - (4-Ethoxy-3-fluorophenyl) -3- (2-oxo) -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-ethoxypyridine) -3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (5-hydroxypyridin-3-yl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - {2 -oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent-4-enoic acid 3 ( R) - {2-Oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent-4- enoic acid 3 (S) - (5-ethoxypyride) In-3-yl) -3- (3- {3- [6- (4-methoxybenzylamino) -pyridin-2-yl] -propyl} -2-oxoimidazolidin-1-yl) -propionic acid 3 (R) - (5-Ethoxypyridin-3-yl) -3- (3- {3- [6- (4-methoxybenzylamino) -pyridin-2-yl] -propyl} -2-oxoimidazolidin-1-yl) -propionic acid 3- {3- [3- (6-Amino-pyridin-2-yl) -propyl] -2-oxo-imidazolidin-1-yl} -3 (S) - (5-ethoxypyridin-3-yl) -propionic acid 3- {3- [3- (6-Amino-pyridin-2-yl) -propyl] -2-oxo-imidazolidin-1-yl} -3 (R) - (5-ethoxypyridin-3-yl) -propionic acid 3 (S) - (2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid,

44 • 444 4 4 4

4 4

4 4

4 4 4

44 3 (R) - (2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5) 3 (S) - (2,3-Dihydro-1H-4, 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -propionic acid -oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl 3-R - (2,3-dihydro-1H-4-oxa-1,5-diazanaphthalen-7-yl) -3- (2-oxo-3) -imidazolidin-1-yl} -propionic acid - (3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3-oxo) -3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1, 5,6,7,8-tetrahydro- 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthalene- 7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - propionic acid 3 (S) - (3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- (3- (5,6,7) 3 (R) - (3,4-Dihydro-2H-1, 8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid -oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- (3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl) 3-S - (furo [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6, 2 H) -imidazolidin-1-yl} -propionic acid 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (furo [2,3-b] pyridin-6-yl) ) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-Dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) 3-R (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5-methyl-propyl) -imidazolidin-1-yl} -propionic acid 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-dihydro) furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrofuro [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzimidazol-2-yl) -3 - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (benzimidazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -p petroleum 1] -imidazolin-1-yl} -propionic acid 3 (S) - (1H-imidazo [4,5-c] pyridin-2-yl) -3- {2-oxo-3- [ 3- (5,6,7,899) 99

9 9 9 9 9 9 9 9

9 9 9

99

9 9 999

3-R - (1H-Imidazo [4,5-c] pyridin-2-yl) -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid ) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (Benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - imidazolidin-1-yl} -propionic acid 3 (R) - (benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] 3 (S) - (1-Methyl-1H-pyrazol-4-yl) -3- (2-oxo-3-) - (naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (1-methyl-1) H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -propionic acid, and pharmaceutically acceptable salts thereof.

Further examples of compounds of the invention include:

3 (S) - (2,3-Dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-) yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (pyridin-3-yl) -3- {2-oxo-3- [ 3- (5,6,7,8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-methoxypyridin-3- yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [eta] &lt; 5 &gt;

- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-methoxyquinolin-7) -yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid , in the form of bis (trifluoroacetate), 3 (S) - (6-methyl-4-aminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [ 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3] - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (furo [2,3-b] Pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1- yl} -propionic acid 3 (S) - (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzimidazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] afthy) (4-Chloro-2-yl) -pentyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzoxazol-2-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, and pharmaceutically acceptable salts thereof.

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, it is • w φ φφ

The nontoxic salts of the compounds of the invention, wherein the nontoxic salts of the compounds of the present invention are: &lt; tb &gt; ______________________________________ &lt; tb &gt; 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, glycollylarsanilate, hexylresorcinates, hydrobamine salts, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, lactobiomates, laurates, malate, maleates, mesylates, methylbromides, methylnitrates, methylsulfates, salts, sulfites, salts, sulfites Nmethyiglucamine ammonium salts, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / hydrogenphosphate blend, polygalacturonate, salicylate, stearate, sulphate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodate, triethiodide, triethiodide. 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. The invention also includes polymorphic forms and hydrates thereof.

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, ανβδ 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 straight or branched chain alkane radical 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 an alkane, containing from 3 to 8 carbon atoms in total and is thus, 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 hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, aryl, arylC 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 1-8 alkyl , C1-6dialkylamino, C1-6-dialkylaminoC1-8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-5alkoxycarbonyl, C1-3alkoxycarbonylC1-6 alkyl, hydroxycarbonylC1-6alkyloxy, hydroxyC1-6alkyl, hydroxy, cyano, trifluoromethyl, oxo or C 1-5 alkylcarbonyloxy. Examples of aryl groups are, for example, phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thianyl,

R 44 44 444 444 furyl, pyrryl, pyrazolyl, dihydrobenzofuryl, benzo (1,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, these groups are unsubstituted or may 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, C 1-3 acylaminoC 1-8 alkyl,

C1-6alkylamino, C1-6alkylaminoC1-8alkyl,

C 1-6 dialkylamino, C 1-6 dialkylaminoC 1-8 alkyl,

C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-5alkoxycarbonyl,

C1-3alkoxycarbonylC1-6 alkyl, hydroxycarbonylC1-6alkyloxy, hydroxy, hydroxyC1-6alkyl, cyano, trifluoromethyl, oxo or C1-5alkylcarbonyloxy. 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, such 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.

7Q

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.

In the case where R ⁷ and R ⁸ include CO, for example C 0-8 alkyl, said group is not present in the substituent when C = 0. Similarly, if any other symbol, such as m, n, t or v is 0, the corresponding group is absent. E.g. when t = 0, - (CH 2) t C = CH is -C -CCH. In addition, when the (C 1-6 alkyl) _p amino group in which p is 0, 1 or 2 may be an amino group, a C 1-6 alkylamino group, or

C1-6dialkylamino. In the case of a C 1-6 dialkylamino group, the alkyl groups may be the same, eg, in a dimethylamino group, or different, eg, in a methylethylamino group. Similarly, a (aryl) _p amino substituent in which p = 0, 1 or 2 may be amino, arylamino and diarylamino and (arylC 1-6 alkyl) _p amino, wherein p is 0, 1 or 2 will be amino, arylC 1-6 alkylamino or di (arylC 1-6 alkyl) amino, wherein the aryl groups may be the same or different.

In the compounds of the invention, the groups R ¹⁰ and R ^{12 may} form, with the carbon atom to which they are attached, a 5- to 7-membered monocyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from the N group , O and S, wherein said ring system is unsubstituted or substituted with one or more substituents R ¹ .

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. When a series of substituents is mentioned, the compound may be 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 fl

-C 1-6 alkyl-NH-C-C 1-5 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.

• 0

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 the α 1β receptor, for example in the prevention or treatment of osteoporosis.

In addition to inhibiting bone resorption, α1β3 receptor antagonism can also produce other effects, such as inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions, viral diseases, tumor growth, or metastasis. However, inhibition of bone resorption is a very prominent effect in α1β3 receptor antagonism.

In particular, antagonism of the α1β5 receptor 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.

I 4 9 4 4 4 4 4 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 · ·· ··· ··· ·· ··

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 manufacture 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 hypercalcaemia in malignant tumors, 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. 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.

· »Fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl

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 pHs, 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 where increased bone resorption occurs, e.g., 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, particularly 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.

• 9 9 9 9 9 9 9 9 9 9

99 99

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 essentially any combination of

And in particular any pharmaceutical composition which is useful for the treatment of 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. They can 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 are commonly manufactured. 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, said 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 of the invention are used in pharmaceutical compositions as active ingredients in admixture with other excipients commonly used for this purpose, such as diluents, carriers and excipients suitable for the dosage form used, e.g., for oral administration tablets, 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.

9999

9 9

9 9

The disintegrant may 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 copolymers, polyhydroxyethylaspartamide and phenol or polyethylene oxide and 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, polydihydropyranes, polycyanoacrylates 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: borane * dimethylsulfide

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 I WANT ₃ : chloroform DBA: bis (dibenzylidene) acetone DEAD: diethylazodicarboxylate DIAD: diisopropylazodicarboxylate 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

• · 00

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.

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. et al., Biorg. Copper. Chem. Letts., 1996, 6, 339-344.

·· 9999

• 9 · 9 9 ♦ 9 9

DETAILED DESCRIPTION OF THE INVENTION

SCHEME 1

1-4 CO ₂ Et l 3

Me

Plf ^ N ^ Ph

H n Bu 1, THF

-Jx. CO ₂ Et

Pn N

Bn 1x5

Pd (OH) ₂ , H ₂

• · * 9 • .99-9

9 9 9

9 9 «• •• 9999

LS: LS

9 «99 • 99 · 99

-bromo-3- (2,2-diethoxy-ethoxy) -benzene (1-2)

To a suspension of sodium hydride (2.77 g, 115.6 mmol) in DMF (100 mL) was added a solution of 3-bromophenol (1-1) in DMF (40 mL) 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 once with 100 ml of 10% aqueous sodium hydroxide solution and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the title compound (1-2) as a yellow oil.

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

1 H NMR (300 MHz, CDCl 3): δ 7.19-7.05 (m, 3H), 6.85 (d, 1H), 4.81 (t, 1H, J = 6.8 Hz), 3, 99 (d, 2H, J = 6.8Hz), 3.71 (m, 4H), 1.22 (t, 6H, J = 7.1Hz).

6-Bromo-benzofuran (1-3)

To a solution of 200 ml of acetal (1-2) in toluene was added 20 g of polyphosphoric acid. The mixture of the two phases was heated to 100 ° C and stirred at 100 ° C for 4 hours. The reaction 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% qo • ΦΦΦΦΦ Φ Φ Φφ 9 9

4 · · Φ * Φ 4 4 9 Φ

ΦΦΦ Φ Φ Φ »» »» »» »» »» »» φ φ φ φ

Hexane solution to give the title compound (1-3) as a yellow oil.

TLC Rf = 0.3 (100% hexanes).

¹ H NMR (300 MHz, CDCl 3): δ 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).

3-Benzofuran-6-yl-acrylic acid ethyl ester (1-4)

A mixture of 1.74 g (8.79 mmol) 6-bromobenzofuran (1-3), 1.09 g (10.98 mmol) ethyl acrylate, 0.099 g (0.44 mmol) 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 are heated in a sealed tube at 100 ° C for 4 hours. The reaction 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. The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to give the ester (1-4) as an off-white solid.

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

1 H NMR (300 MHz, CDCl 3): δ 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 = 8.4Hz), 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 = 7.2Hz).

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

A solution of 1.32 g (6.30 mmol) of N-benzyl-α- (R) -methylbenzylamine in 25 mL of tetrahydrofuran at 0 ° C was treated with 2.52 mL of a 2.5 M solution of n-butyllithium in a mixture of hexanes. The resulting solution is stirred for 30 minutes at ♦ · · · · · · · · · · · · · · · ·

Β Β φ Φ Φ

The temperature is 0 ° C, and then cooled to -78 ° C. A solution of 0.681 g (3.15 mmol) of acrylate (1-4) in 5 mL of tetrahydrofuran was added and the mixture was stirred at -78 ° C for 15 min, then 5 mL of saturated aqueous ammonium chloride solution was added and the cooling bath was removed. The reaction mixture was allowed to warm 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 10% ethyl acetate in hexanes to give β-aminoester (1-5) as a yellow oil.

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

1 H NMR (300 MHz, CDCl 3): δ 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).

3 (S) -Amino-3- (2,3-dihydro-benzofuran-6-yl) -propionic acid ethyl ester (1-6)

A mixture of 1.19 g (2.78 mmol) of dibenzylamine (1-5) in a mixture of 26 ml of ethanol, 3 ml of water and 1.0 ml of acetic acid is degassed with argon and treated with 1.19 g of palladium hydroxide. . The reaction mixture was hydrogenated at a hydrogen pressure of 1 bar. After stirring for 18 hours, the reaction mixture was diluted with ethyl acetate and filtered through celite. After concentration of the filtrate, the residue was purified by flash chromatography eluting with 10% ethyl acetate in dichloromethane to give the ester (1-6) as a white solid.

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

¹ H NMR (300 MHz, CD 3 OD) as trifluoroacetate: δ 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).

0 ···· ♦ 0

0 0 0 0 0

0 0 0

00

Scheme 2

hci * h ₂ n.

OEt

NaB (OAc) 3H

NEt3

boc ₂ o

DMAP (cat) 'N

Qg _t acetone TsOH ⁰ A, ⁰ A 2 = tBuO 2 heating

2 = 2

O

O

OEt

IN?

¢ 3

4444 ·· 4

4 4 4

44

Scheme 2 (Part 2)

1) NaOH, HCl

2) EDC, HOBT, NEt ₃ / OCH ₃

HCl-HN.

CH ₃

2-9A

»9« 4 ·· 99 ty ·

* 9 9 4 ·· 99

HCl (g)

2 = 1ώ _

2Δ1

NaOH aqueous solution NaHCO ₃ COCl _2> CH ₂ C1 ₂ -

2-13 incl

• 9 • • «9 • 99 99 • • 9 9 · 9 9 9 9 • 9 • 9 • • 9 « 9 9 9 9 • • • 9 9 9 9 9 9 9 «9 • 9 99 9 • 99 99 99

4-Oxo-pentanoic acid methoxy-methylamide (2-1)

To a stirred solution of 30 g (0.258 mol) of levuic acid in 850 ml of chloroform at 0 ° C was added, over 15 minutes, 43.2 ml (0.310 mol) of triethylamine, followed by 37 ml (0.284 mol) of isobutyl chloroformate. After 30 minutes, 57.6 ml (0.413 mol) of triethylamine was added, followed by 37.8 g (0.387 mol) of Ν, Ο-dimethylhydroxylamine hydrochloride in five portions over 5 minutes. After gas evolution, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated to a wet solid by rotary evaporation under reduced pressure. The resulting residue was suspended in 500 ml of ethyl acetate, washed with 10% potassium carbonate solution, saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave the title product (2-1) as a yellow oil.

TLC Rf = 0.42 (silica, 1: 1 chloroform / ethyl acetate).

¹ H NMR (300 MHz, CDCl 3): δ 3.74 (s, 3H), 3.18 (s, 3H), 2.65-2.95 (m, 4H), 2.21 (s, 3H) .

N-Methoxy-N-methyl-3- (2-methyl- [1,3] dioxolan-2-yl) -propionamide (2-2)

To a solution of the resulting amide (2-1) (38 g, 0.239 mol) in benzene (500 ml) was added ethylene glycol (17.3 ml, 0.310 mol) and p-toluenesulfonic acid (1 g). The reaction mixture was heated to reflux for 2 hours while removing water by azeotropic distillation. After cooling, the solution is washed with 200 ml of saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave the title compound (2-2) as a yellow oil.

TLC Rf = 0.62 (silica, ethyl acetate).

1 H NMR (300 MHz, CDCl 3): δ 3.95 (m, 4H), 3.68 (s, 3H), 3.17 (s, 3H),

2.51 (t, 2H, J = 8Hz), 2.00 (t, 3H, J = 6Hz) 1.33 (S, 3H).

3- (2-Methyl- [1,3] dioxolan-2-yl-propionaldehyde (2-3)

To a solution of the resulting product (2-2) (44.74 g, 0.22 mol) in tetrahydrofuran (400 mL) at -78 ° C was added 264 mL (0.264 mol) of 1M DIBAL in hexanes over 10 min. After stirring for 1 hour, 350 ml of a 1.0 M solution of Rochelle salt and 300 ml of ether are added, followed by removal of the cooling bath. After stirring for 1 hour, the organic portion was separated and dried over sodium sulfate. Evaporation of the solvent afforded (2-3) as a colorless oil.

TLC Rf = 0.80 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl 3): δ 9.73 (s, 1H), 3.50 (d, 1H, J = 16 Hz),

2.61 (d, 1H, J = 21Hz), 2.48 (m, 1H), 2.07 (t, 1H, J = 7H), 1.33 (s, 3H).

[3- (2-Methyl- [1,3] dioxolan-2-yl) -propyl-amino] -acetic acid ethyl ester (2-4)

To a solution of 31.7 g (0.22 mol) of the resulting product (2-3) in 1000 ml of 1,2-dichloroethane at 0 ° C was added 61.5 g (0.44 mol) of glycine ethyl ester hydrochloride, 107 ml. (0.77 mol) triethylamine and 65.3 g (0.308 mol) NaB (OAc) 3H. The reaction mixture was allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was evaporated to one third of the initial volume, diluted with ethyl acetate, and then washed with 10% potassium carbonate solution, saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography eluting with mixtures.

9999

9 9 • 9 9 • 9 9 • 9 «9

999

999 9 9 9 9 9 chloroform / ethyl acetate 1: 1, followed by 5% methanol in ethyl acetate to give the title product (2-4) as a yellow oil.

TLC Rf = 0.40 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl 3): δ 6.01 (br s, 1H), 4.21 (m, 3H), 4.03 (d, 1H, J = 5 Hz), 3.93 (m, 4H), 2.62 (t, 2H, J = 8Hz), 1.53-1.67 (m, 4H),

1.29 (m, 6H).

{tert-butoxycarbonyl- [3- (2-methyl- (1,3) -2-dioxolan-2-yl) propyl] amino} acetic acid ethyl ester (2-5)

To a solution of 24 g (0.104 mol) of the resultant product (2-4) in 100 ml of tetrahydrofuran was added trace amounts of 4- (dimethylamino) pyridine, 20 drops of triethylamine and 23.8 g (0.109 mol) of BOC2O. After 4 hours and evaporation of the solvent, the title product (2-5) was obtained as a colorless oil.

TLC Rf = 0.38 (silica, 30% ethyl acetate in hexane).

1 H NMR (300 MHz, CDCl 3, mixture of rotamers): δ 4.22 (m, 3H), 3.93 (m, 4H), 3.27 (m, 2H), 1.63 (m, 4H), 1 51 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H), 1.31 (s, 3H), 1.28 (m, 4H).

[tert-Butoxy-carbonyl- (4-oxo-pentyl) -amino] -acetic acid ethyl ester (2-6)

To a solution of 35 g (0.1 mol) of the resultant product (2-5) in 600 ml of acetone was added 1 g of p-toluenesulfonic acid. The reaction mixture was heated to reflux for 2 hours. After cooling, the reaction mixture is evaporated to one fifth of the initial volume, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave the product (2-6) as a yellow oil.

TLC R f = 0.31 (silica, 30% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl 3, mixture of rotamers): δ 4.20 (m, 2H), 3.92 (s, 0.85H), 3.83 (s, 1.15 H), 3.3 ( m, 2H), 2.52 (m, 2H), 2.14 (s, 3H), 1.78 (m, 2H), 1.51-1.42 (3s, 9H), 1, 28 (m, 3 H).

[tert-Butoxycarbonyl- (3- [1,8-naphthyridin-2-yl-propyl) -amino] -acetic acid ethyl ester (2-7)

A solution of the resulting product (2-6) (28 g, 97.4 mmol), 2-amino-3-formylpyridine (15.5 g, 127 mmol) and proline (11.2 g, 97.4 mmol) in ethanol (15 mL) was added at room temperature. The mixture was heated at reflux for 1 hour. After cooling and evaporation, the resulting residue was purified by silica gel column chromatography eluting with 1: 1 chloroform: ethyl acetate to give the title product (2-7) as a yellow oil.

TLC Rf = 0.41 (silica, chloroform / ethyl acetate / methanol 70: 25: 5)

1 H NMR (300 MHz, CDCl 3): δ 9.09 (m, 1H), δ, [1.4] (m, 2H), 7.43 (m, 2H), 4.17 (q, 2H, 7) Hz), 3.9 (2s, 2H), 3.43 (q, 2H, J = 7Hz), 3.07 (m, 2H), 2.18 (m, 2H), 1.42 (s, 9H), 1.25 (m, 3H).

{tert-butoxycarbonyl- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -amino} -acetic acid ethyl ester (2-8)

A solution of 24.3 g (65.1 mmol) of the title product (2-7), 4 g of platinum oxide and 130 ml of ethanol was hydrogenated under a hydrogen atmosphere for 6 hours. After filtration and evaporation, the resulting residue was purified by silica gel column chromatography eluting with ethyl acetate to give the title product (2-8) as a yellow oil.

TLC Rf = 0.35 (silica, chloroform / ethyl acetate / methanol 70: 25: 5)

9?

• · · 4

4 44

1 H NMR (300 MHz, CDCl 3): δ 7.05 (d, 1H, J = 6 Hz), 6.37 (m, 1H), 4.74 (brs, 1H), 4.18 (q, 2H, J = 7Hz), 3.9 (2s, 2H), 3.32 (m, 4H), 2.63 (m, 2H), 2.51 (m, 2H), 2.72 (m, 4H) 1.43 (m, 9H); 1.26 (m, 3H).

((Methoxy-methyl-carbamoyl) -methyl) - (3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl) -carbamic acid tert-butyl ester (2-9)

To a solution of 1.49 g (3.96 mmol) of the resultant product (2-8) in 8 mL of ethanol was added 4.36 mL (4.36 mmol) of a 1M solution of sodium hydroxide in water. After stirring at 50 ° C for 1 h, 4.75 mL (4.75 mmol) of a 1M solution of hydrochloric acid in water was added and the reaction mixture evaporated to an oily residue. The residue is evaporated three times from ethanol and then three times from acetonitrile to give a yellow solid, which is dried under vacuum at less than < 266 Pa for 2 hours. This residue was suspended in 15 ml of chloroform, and 2.75 ml (19.8 mmol) of triethylamine, 0.772 g (7.92 mmol) of N, Odimethyl-hydroxyl-amine hydrochloride, 1 g of HOBT and 0 g of ethyl acetate were added to the suspension. , 91 g (4.75 mmol) EDC. After stirring for 15 hours, the reaction mixture is evaporated to dryness, the residue is suspended in ethyl acetate, washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave the title product (2-9) as a yellow oil.

TLC Rf = 0.49 (silica, chloroform / ethyl acetate / methanol 70/25/5).

1 H NMR (300 MHz, CDCl 3): δ 7.05 (m, 1H), 6.38 (m, 1H), 4.81 (br s, 1H), 3.69, m, 3H), 3.37 (m, 4H), 3.18 (s, 3H), 2.64 (m, 2H), 2.53 (m, 2H), 1.88 (m, 4H), 1.44 (m, 9H) .

• • •

S00 {tert-butoxycarbonyl- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -amino} -acetaldehyde (2-9A)

To a stirred solution of the resulting product (2-9) (11.0 g, 28.0 mmol) and tetrahydrofuran (300 mL) was added dropwise a 1M solution of DIBAL in hexanes (42 mL, 42 mmol) at -78 ° C over 20 min. After 1.0 hour, 300 mL of 1.0 M Rochelle salt solution was added, followed by removal of the cooling bath. The reaction mixture was stirred for 1.0 hour and then diluted with diethyl ether. After stirring for 30 minutes, the organic portion was separated and dried over magnesium sulfate. Evaporation of the solvent gave the crude aldehyde (2-9A) as a colorless oil.

TLC Rf = 0.34 (silica, chloroform / ethyl acetate / methanol 75/25/5).

ethyl 3 (S) - (2- {tert-butoxycarbonyl- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)) - propyl] -amino} -ethyl- amino) -3- (2,3-dihydro-benzofuran-6-yl) -propionic (2-10)

A mixture (9.1 mmol) of crude aldehyde (2-9A), 3.2 g (11.8 mmol) of the resultant product (1-6), 3 g of molecular sieves as a powder and 100 ml of DCE was stirred for 30 minutes. The reaction mixture was cooled to 0 ° C and then 2.7 g (12.7 mmol) of NaB (OAc) 3 H was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and then washed with 10% potassium carbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent left a residue which was purified by silica gel column chromatography eluting with 1-3% ethanol / ammonium hydroxide / water (10: 10: 1) in chloroform / ethyl acetate (50:50) to give the title product (2-10). ) as a yellow oil.

9 9 9 9 9 99 99 99 99 9 9 9

9 9 9 9 9 9 9 9 9 99 999 99 99 99

TLC Rf = 0.23 (silica, 5% ethanol, ammonium hydroxide and water 10: 10: 1 in chloroform / ethyl acetate 50:50) @ ¹ H NMR (300 MHz, CDCl3): .delta.7, 10 (d, J = 7.6Hz, 1H), 7.04 (d, J = 7.3Hz, 1H), 6.75 (m, 2H), 6.31 (d, J = 7.3) Hz, 1H), 4.76 (s, 1H), 4.55 (t, J = 8.6 Hz, 2H), 4.08 (m, 2H), 4.00 (t, J = 6.1 Hz, 1H), 3.41 (m, 2H), 3.16 (m, 6H), 2.68 (t, J = 6.4 Hz, 1H), 2.59 (m, 3H), 2, 48 (t, J = 7.6Hz, 2H), 1.81 (m, 4H), 1.39 (s, 9H), 1.21 (m, 3H).

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethyl ester -propylamino] -ethylamino-propionic (2-11)

Hydrogen chloride gas was bubbled through a solution of 4.0 g (7.2 mmol) of the title product (2-10) in 160 mL dioxane at 0 ° C for 10 min. After 30 minutes, argon was bubbled through the solution for 30 minutes. The solution was concentrated to give the yellow amine solid (211).

1 H NMR (300 MHz, CDCl 3): δ 7.91 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H) 7.10 (m, 2H), 6.56 (d, J = 6.1 Hz, 1H), 4.58 (m, 2H), 4.04 (m, 2H), 3.49 (m, 4H) 3.19 (m, 2H), 2.90 (m, 2H), 2.79 (m, 2H), 2.30 (m, 2H), 1.98 (m, 2H), 1.85 (m, 2H) m, 5H), 1.15 (t, J = 7.1Hz, 3H).

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridine) ethyl ester -2-yl-propyl] -imidazolidin-1-yl} -propionic (2-12)

To a stirred solution of the resulting product (2-11) (11.8 mmol), methylene chloride (20 mL) and potassium carbonate (20%) was added, dropwise, a 1.93 M solution of phosgene in toluene (1.93 M, 13 mL). After stirring for 30 minutes, the organic portion was separated and dried (O 2).

over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography eluting with 5-10% methanol in ethyl acetate to give a yellow oil of the product (ΣΙ 2). TLC Rf = 0.25 (70:20:10 silica, chloroform / ethyl acetate / methanol)

1 H NMR (300 MHz, CDCl 3): δ 7.12 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.34 (d, J = 7.3 Hz, 1H), 5.46 (t, J = 7.9 Hz, 1H), 4 74 (s, 1H); 4.55 (t, J = 8.9 Hz, 2H); 4.10 (q, J = 7.3 Hz, 2H); 3.41 (m, 2H); 21 (m, 6H), 2.95 (m, 3H), 2.67 (t, J = 6.1 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H), 1 88 (m, 5H), 1.20 (t, J = 7.3 Hz, 3H).

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine] -in- 2-yl) -propylimidazolidin-1-yl} -propionic acid (2-13)

To a solution of the resulting ethyl ester (2-12) (2.9 g, 6.06 mmol) in ethanol (15 mL) was added 1 N sodium hydroxide (7.2 mL, 7.2 mmol). After stirring for 2 hours, the solvent was evaporated and the residue was purified by silica gel column chromatography eluting with a 25: 10: 1: 1 mixture of ethyl acetate, ethanol, water and ammonium hydroxide followed by 15: 10: 1: 1 to give the title product ( 2-13) as white solids.

TLC Rf = 0.24 (15: 10: 1: 1 ethyl acetate / ethanol / water / ammonium hydroxide).

¹ H NMR (300 MHz, CD 3 OD): δ 7.55 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.81 (d, J) = 6.1 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.38 (t, J = 7.9 Hz, 1H), 4.53 (t, J = 8.9 Hz, 2H), 3.14 → 3.53 (9H), 2.97 (m, 3H), 2.80 (t, J = 6.1 Hz, 2H), 2.67 (t, J = 7.3Hz, 2H), 1.93 (m, 4H).

• · · · · · · · · · · · · ·

X03 • · · · ··· ·

Scheme 3

Ph ₃ PCHCO ₂ Et / V-CHO CH ₂ Cl ₂

H

Ph ^^ N ^ / Ph

AND

Me

THF

2. nBuLi, THF

3. H ₂ O ^p \

1.Pd (OH) ₂ , H ₂ , EtOH, HOAc, H ₂ O

2. HCl, ether

Ethyl 3-fluoro-cinnamate (3-2)

To a solution of 18.16 g (146 mmol) of 3-fluorobenzaldehyde (3-1) in 500 mL of dichloromethane was added 61.2 g (176 mmol) of ethyl (triphenylphosphoranylidene) acetate, and the resulting solution was stirred at room temperature for 18 hours. After evaporation of the solvent, the residue is mixed with a mixture of ether in hexane and filtered. The filtrate was concentrated and then purified on a silica gel column eluting with a 9: 1 mixture of hexane and ethyl acetate. Removal of the solvent gave the title product (3-2) as an oil (-95% trans), which was used in the next synthesis without further purification.

1 H NMR (300 MHz, CDCl 3): δ 1.36 (3H, t), 4.28 (2H, q), 6.43 (1H, d), 7.08 (1H, m), 7.2- 7.4 (3H, m); 7.64 (1H, d).

N-benzyl- (R) -α-methylbenzyl-3 (S) -fluoro-phenyl-3-alanine ethyl ester (3-3)

To a solution of 33.4 g (158 mmol) of N-benzyl- (R) -α-methylbenzylamine in 450 mL of tetrahydrofuran at 0 ° C was added 99 mL (158 mmol) of a 1.6 M solution of n-butyllithium in a mixture of hexanes. The dark violet solution was stirred at 0 ° C for 30 min, cooled to -78 ° C, and 29.2 g (150 mmol) of the resulting ester (3-2) in 100 mL of tetrahydrofuran was added over 5 min. The resulting solution was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature. After 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and then brine, the product is dried and concentrated in vacuo to an oil. The product was purified by silica gel column chromatography eluting with hexane / ethyl acetate (1: 1) then pure ethyl acetate to give the title product (3-3).

¹ H NMR (300 MHz, CDCl 3): δ 1.06 (3H, t), 1.28 (3H, d), 2.52 (1H, dd),

2.62 (1H, dd), 3.66 (1H, d), 3.72 (1H, d), 3.95 (2H, q), 4.44 (1H, dd), 6.95 (1H , m), 7.1-7.5 (13H, m).

3 (S) -Fluoro-phenyl-3-alanine ethyl ester hydrochloride (3-4)

A solution of 28.2 g (69.6 mmol) of N-benzyl- (R) -. Alpha.-methylbenzylamine (3-3) in 300 ml of ethanol, 30 ml of acetic acid and 3 ml of water was degassed with argon over 30 minutes. To the mixture was added 2.6 g of palladium hydroxide on charcoal (20% dry weight) and the mixture was then stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite and the solvent was removed in vacuo to give an oil. This oil was dissolved in 200 mL of ether, and 60 mL of 1N HCl in ether was added to form a precipitate. Filtration and washing of the solid with a mixture of ether and hexane gave the title compound (3-4) as a white solid.

¹ H NMR (300 MHz, CD ₃ OD): δ 1.21 (3H, t), 3.0-3.2 (2H, m), 4.16 (2H, q), 4.76 (1H, t), 7.2-7.35 (3H, m), 7.5 (1H, m).

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

Compound (3-5) was prepared using intermediates of compound (3-4) according to the procedure for preparing compound (2-13).

TLC Rf = 0.36 (ethyl acetate: ethanol: water: ammonium hydroxide = 15: 10: 1: 1). 1 H NMR (300 MHz, CD 3 OD): δ 7.41 (m, 2H), 7.09 (m, 3H), 6.54 (d, 1H, J = 8.2 Hz), 5.48 (m, 1H), 3.51 (m, 2H), 3.46 (m, 3H), 3.23 (m, 2H), 2.94 (m, 2H), 2.81 (m, 4H), 2, 63 (m, 2H), 1.93 (m, 2H), 1.19 (m, 2H, J = 5.1 Hz).

• 4 · 4 · 4 · 4 · 4

4 4 4

44

Scheme 4 «· 4« 44 • 4 «4» ♦ ». ♦

4 4 *

4 4 4

4 4 4 4

Penicillin amidase (EC 3.5.1.11) pH = 7.8, H ₂ 0

4-4

4-7

EtOH, HCl 95%

6N HC! Deň: 32 ° C

4-6 · ♦ ····

3-Quinolin-3-yl-propionic acid (4-2)

A solution containing 5 g (31.8 mmol) of quinofine-3-carboxaldehyde (4-1), 3.6 g (35.0 mmol) of malonic acid and 5.0 g (63.6 mmol) was heated at reflux for 12 h. of ammonium acetate in 125 ml of anhydrous ethanol. After cooling to room temperature, the white solid formed was collected by filtration and washed with 150 mL cold ethanol, and then dried in vacuo to give the product (4-2) as 3.84 g (17.8 mmol) of white solid in yield. 56%.

¹ H NMR (300 MHz, D 2 O): δ 8.91 (d, J = 2 Hz, 1H), 8.21 (d, J = 2 Hz, 1 H), 8.12 (d, J = 8 Hz, 1 H) ), 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-Phenylacetylamino-3-quinolin-3-yl-propionic acid (4-3)

To a solution of 3.5 g (16.2 mmol) of the resultant product (4-2) and 2.7 g (32.4 mmol) of sodium bicarbonate in 100 ml of a 50% aqueous dioxane solution cooled to 0 ° C was added. dripped with solution

3.00 g (19.4 mmol) of phenylacetyl chloride in 25 ml of dioxane. Created by ·· ♦ ·

9

The solution was stirred at 0 ° C for 2.5 hours and then allowed to warm 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, followed by extraction three times with 150 ml of methylene chloride. The organic extracts were dried, filtered and concentrated to give the product (4-3) as an off-white solid.

1 H NMR (300 MHz, CD 3 OD): δ 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- (S) -quinolin-3-yl-propionic acid dihydrochloride (4-6)

5.0 g (15 mmol) of acid (4-3) are suspended in 3.5 l of water and the resulting suspension is treated with 15 ml of 1N sodium hydroxide solution to give the product as a clear solution. After addition of 10,000 U penicillin amidase (Sigma, EC 3.5.1.11) in 0.1 M phosphate buffer solution, the pH of the reaction mixture was brought to 7.8 by addition of 1 N sodium hydroxide solution. The solution was stirred at room temperature for 4 days. The reaction is monitored regularly by HPLC, and the reaction is complete after 50% conversion. The solution was then cooled to 0 ° C and brought to pH = 3 by addition of 3N hydrochloric acid solution. The yellow oily precipitate was collected by filtration and then washed with water to give 1.8 g (5.3 mmol) of crude product (4-5). The filtrate was extracted three times with 500 mL of methylene chloride to give an additional portion (4-5) of the product with phenylacetic acid.

Both portions of the crude product (4-5) were combined and the product was stirred for 12 hours in 200 mL of 3 N hydrochloric acid (200 mL) at 50 ° C. After cooling and washing twice with 100 ml of ether, the product was evaporated to give the product (4-6).

• ♦ · · · «

1 1 a a · a

8 and 8 and 8 and 18 and 18 and 11, 11-propionic acid ethyl ester dihydrochloride (4-7)

3- (S) -quinolin-3-yl The obtained acid (4-6) is converted to the product (4-7) by heating to reflux in the presence of an ethanolic hydrochloric acid solution.

¹ H NMR (300 MHz CD 3 OD): δ 9.25 (d, J = 2 Hz 1H), 8.31 (d, J = 2 Hz, 1H), 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).

3- (S) - (Quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl 1-Imidazolidin-1-yl} -propionic acid (4-8)

Compound is prepared using the product (4-7) according to the procedure for the preparation of compound (2-13).

1 H NMR (300 MHz, CD 3 OD): δ 8.83 (m, 1H), 8.32 (m, 1H), 8.02 (m, 2H), 7.78 (m, 1H), 7.63 ( m, 1H), 7.43 (d, 1H, J = 7.3 Hz), 6.57 (d, 1H, J = 7.3 Hz), 5.76 (m, 1H), 3.73 ( q, 1H, J = 8.2 Hz), 3.48 (m, 3H), 3.32 (m, 4H), 3.17 (m, 2H), 2.95 (m, 1H), 2, 84-2.62 (6H), 2.10 (m, 1H), 1.88 (m, 3H).

Scheme 5

3 (S) - (Pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl] -imidazolidin-1-yl} -propionic acid (5-2)

Compound (5-2) was prepared using intermediates of compound (5-1) (Zablocki et al., J. Med. Chem. 1995, 38, 2378) according to the procedure for preparing compound (2-13).

1 H NMR (300 MHz, CD 3 OD): δ 8.54 (m, 1H), 8.47 (m, 1H), 7.85 (d, 1H, J = 7.9 Hz), 7.46 (m, 2H), 6.55 (d, 1H, J = 7.3Hz), 5.57 (m, 1H), 3.63 (m, 2H), 3.46 (m, 3H), 3.18 (m) m, 2H), 3.01 (m, 2H), 2.77 (m, 4H), 2.60 (m, 2H), 2.05 (m, 1H), 1.93 (m, 3H).

TLC (silica): Rf 0.09 (ethyl acetate: ethanol: ammonium hydroxide:

Water = 15.10: 1) • 4 ·

4 4

4 4 4

4- · 4

Scheme 6

2x3 hci-h ₂ n.

OEt ch ₃

NaB (OAc) gH

NEt ₃ ///

CH ₃

OEt ₂ of boc

DMAP (Cat.)

OEt acetone, TsOH heating

OEt cc °

NH ₂

OEt

Pd / C, H ₂ EtOH proline EtOH; and then BOC2O

OEt

N.

9 «9»

<

Scheme 6 (2nd part)

1) NaOH, HCl

2) EDC, HOBT, NEt ₃

1) DIBAL

2) NaB (OAc) ₃ H

NEtg, JhI • OCH _:

CHq

N Ν 'H

6-10

6-11

99

9 9 4

9 9 9 4

9 «4

9 9 9

9999 * 9

9 9

9 · 99

Scheme 6 (Part 3)

6-11

Aqueous NAHCO3 solution

COC1 ₂₎ ch ₂ or ₂

OE

The imidazoline ring of the methylated compound (6-13) was prepared according to the procedure described in Scheme 2 by replacing the glycine ethyl ester with the alanine ethyl ester.

The invention also relates to other imidazoline ring substitution systems prepared according to Scheme 2 using the desired naturally occurring or laboratory prepared amino acids.

Scheme 7

Br ₂ , KBr, KOH H ₂ O

Pd (OAc) ₂ , Et ₃ N, tri-o-tolylphosphine ethyl acrylate, methyl cyanide

7-3

Ph

Ph

1.

Me

THF

2. nBuLi, THF

3. NH ₄ Cl, H ₂ O

H ₂ N

Pd (OH) ₂ , H ₂ , EtOH, HOAc, H ₂ O

CO ₂ Et

MeO

7-5

9 9 9 9 9 to 9 9 1 9 9.1

Scheme 7 (2nd part)

2-9A

NaCNBH 6, HOAc NaOAc, 4Å sieves i-PrOH

Boc

AND

N HN V_7

MeO

OEt

HCl, EtOAc

OEt

IN_/

DIPEA, DMAP CH ₂ CICH ₂ CI

NaOH MeOH, H ₂ O

OH • 44 ·· · 4 · 4 · 4 · 4 44 · 444

4 4 4 4 4

4 4 · 4 • 44

5-Bromo-2-methoxypyridine (7-2)

To a solution of 4.2 g (0.075 mol) of potassium hydroxide in 750 ml of water was added 16.4 g (0.15 mol) of 2-methoxypyridine (7-1), followed by dropwise addition of 24 g (0.15 mol) of bromine in 750 ml of 1N aqueous potassium bromide solution and the resulting solution was stirred at room temperature for 5 hours. Solid sodium bicarbonate was added to the basic pH and the solution was extracted three times with 500 mL of hydrochloric acid. The organic portion was washed with 10% sodium bisulfite solution and then with saturated sodium chloride solution. After drying over sodium sulfate, the product was filtered and the solvent was removed in vacuo. The dark brown oil formed predominantly contained the desired compound (7-2) which was used in the next synthesis 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 (1H, d).

ethyl 3- (6-methoxypyridin-3-yl) acrylate (7-3)

A solution of 74.3 g (0.4 mol) of 5-bromo-2-methoxy-pyridine (7-2), 150 ml (1.4 mol) of ethyl acrylate, 150 ml (1.08 mol) of triethylamine, 10 g (0.045 mol) palladium (II) acetate and 20 g (0.066 mol) of tri-o-tolylphosphine in 100 ml of acetonitrile are degassed for 10 minutes in the presence of argon. The reaction mixture was heated at 90 ° C for 12 hours and then the volatiles were removed in vacuo. Toluene (300 ml) was added and the reaction mixture was concentrated again. After addition of 300 ml diethyl ether, the reaction mixture was filtered through a pad of silica gel, eluting with 800 ml diethyl ether. The diethyl ether was removed and the resulting residue was purified by silica gel column chromatography eluting with ethyl acetate / hexane (1:19, 1:14 and 1: 9) to give compound (7-3) as a yellow solid.

»9

9 · 99

9 9 • 9 9 9 9 9

999 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-methylbenzyl-3 (S) - (6-methoxypyridin-3-yl) -β-alanine ethyl ester (7-4)

To a solution of 97.5 g (462 mmol) of N-benzyl- (R) -α-methylbenzylamine in 750 mL of tetrahydrofuran at 0 ° C was added 178.5 mL (446 mmol) of a 2.5 M solution of n-butyllithium in the mixture hexanes. The dark violet solution was stirred at 0 ° C for 20 minutes, cooled to -78 ° C over a period of 60 minutes, and 63.7 g (308 mmol) of ester (7-3) in 250 mL of tetrahydrofuran was added. The resulting solution was stirred at -78 ° C for 1 hour, then transferred via cannula to a saturated ammonium chloride solution and extracted with ethyl acetate, washed with water, then a saturated sodium chloride solution. Drying and concentration in vacuo gave an oil which was purified by silica gel column chromatography eluting with hexane / ethyl acetate 9: 1 then 4: 1. The product (7-4) is obtained as an oil with N-benzyl- (R) -. Alpha.-methylbenzylamine. 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 (7-4).

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).

3 (S) - (6-Methoxy-pyridin-3-yl) -3-alanine ethyl ester (7-5)

To a solution of 70 g of ester (7-4) in 250 ml of ethanol, 25 ml of acetic acid and 2 ml of argon-degassed water is added 20% hydroxide solution

9 · 9999 • 9 ·· • 9 • 9 9 «9 • · 9 9 • 9 • 9 • • 9 9 9 9 9 • • 99 9 9 9 9 · 9 99 9 • 9 99 < * · 9 9 99 9

palladium on activated carbon. The reaction mixture was placed under an atmosphere of hydrogen and the resulting mixture was stirred for 24 hours. After filtration through celite and washing with ethyl acetate, the solvent was removed in vacuo to give the product as a waxy white solid. This product was dissolved in 200 ml of water and extracted twice with 200 ml of diethyl ether. The aqueous portion was then treated with solid potassium carbonate to complete saturation and 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 (7-5) 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) - (2- {tert-Butoxy-carbonyl- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl] -amino} -ethylamino) -3-ethyl ester 2-Methoxy-pyridin-5-yl) -propionic acid (7-6)

To a solution of 6.85 g (30.5 mmol) of the amine (7-5) in 300 mL of 2-propanol at room temperature was added 1.75 mL (30.5 mmol) of acetic acid, 24.6 g (0.3 mL). mol) of sodium acetate and 5 g of molecular sieves with a mesh size of 4A. After addition of 8.1 g (24.3 mol) of aldehyde (2-9A) in 150 ml of 2-propanol, the mixture was stirred for 15 minutes, cooled to 0 ° C, and then 5.66 g (90 mmol) was added in one portion. ) sodium cyanoborohydride. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was filtered through celite and the solvent removed in vacuo to give a residue which was treated with a 10% aqueous potassium bisulfite solution for 30 minutes. The reaction mixture was brought to basic pH by addition of solid potassium carbonate (pH ~ 10) and extracted three times with 200 ml of ethyl acetate. The ethyl acetate portions were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo to give an oil. This product is purified ·· · <

9 9

9 9

9 · ·

9 9

999 «··; W}

9999

9 9

9 9

9 9 9

9 9 9

Silica gel column chromatography eluting with 5% methanol in chloroform gave the product (7-6) as an oil containing approximately 7% β-alanine.

¹ H NMR (300 MHz, CDCl 3): d 1.20 (3H, t), 1.42 (9H, s), 1.7-2 (4H, br m), 2.5-2.8 (SH m), 3.2 (4H, m), 3.42 (2H, m), 3.92 (3H, s), 4.06 (2H, q), 5.0-5.4 (1H, bs), 6.36 (1H, br s), 6.72 (1H, d), 7.12 (1H, br s), 7.58 (1H, dd), 8.07 (1H, d).

3 (S) - (6-Methoxy-pyridin-3-yl) -3- {2- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl-amino] -ethylamino-ethyl ester } -propionic acids (7-7)

A solution of the ester (7-6) of 14.1 g (26 mmol) in ethyl acetate (350 mL) was cooled to -20 ° C. The cooled solution was treated with gaseous hydrochloric acid for 10 minutes, then capped and stirred at 0 ° C for 1.5 hours. The volatiles were removed in vacuo, the residue was taken up in 150 ml of water and the mixture was brought to pH approximately 10 by addition of solid potassium carbonate. The solution was extracted three times with 150 ml of ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to an oil.

This product was purified by silica gel column chromatography eluting with 5% methanol in chloroform to give β-alanine (7-5). Further elution with 5% methanol in ammonia saturated chloroform gave the product (7-7) as a viscous oil.

¹ H NMR (300 MHz, CDCl 3): d 1.20 (3H, t), 1.8-1.95 (4H, m), 2.5-2.8 (12H, m), 3.39 ( 2H, m), 3.92 (3H, s), 4.09 (2H, q), 5.01 (1H, bs), 6.34 (1H, d), 6.72 (1H, d), 7.06 (1H, d), 7.59 (1H, dd), 8.07 (1H, d).

3 (S) - (6-Methoxy-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -ethyl ester -propylimidazolidin-1-yl} -propionic (7-8)

120

ΦΦΦΦΦΦ φ φ φ φ · · · · · ·

To a solution of 8.03 g (18.2 mmol) of diamine (7-7), 9.5 mL (54.6 mmol) of DIPEA and 250 mg of 4- (dimethylamino) pyridine in 150 mL of 1,2-dichloroethane cooled to at -20 ° C, 3.85 g (19.1 mmol) of p-nitrophenyl chloroformate in 25 ml of 1,2-dichloroethane was added dropwise so that the internal temperature of the mixture remained below -15 ° C. The resulting mixture was allowed to warm to 0 ° C and stirred for 45 minutes, then heated at reflux for 4 hours. After cooling and evaporation of the solvent in vacuo, the residue is taken up in ethyl acetate and thoroughly washed six times with 150 ml of 10% potassium carbonate solution and once with saturated sodium chloride solution. The ethyl acetate portion was dried over sodium sulfate and concentrated in vacuo to give 6.27 g of an oil which was purified by silica gel column chromatography eluting with 5% ethanol in methylene chloride to give the product (7-8) as an oil.

¹ H NMR (300 MHz, CDCl 3): d 1.20 (3H, t), 1.8-1.95 (4H, m), 2.52 (2H, dd), 2.68 (1H, dd) 2.9-3.1 (3H, m), 3.15-3.3 (5H, m), 3.39 (2H, m), 3.92 (3H, s), 4.11 (2H) (q), 4.8 (1H, bs), 5.42 (1H, t), 6.34 (1H, d), 6.72 (1H, d), 7.03 (1H, d), 7 60 (1H, dd); 8.08 (1H, d).

3 (S) - (6-Methoxy-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl -imidazolidin-1-yl} -propionic acid (7-9)

To a solution of 3.48 g (7.4 mmol) of ester (7-8) in 50 mL of methanol and 30 mL of water at room temperature was added 22.3 mL (22.3 mmol) of 1N sodium hydroxide solution and the reaction mixture was stirred at room temperature. hours of stirring. After removal of the solvent in vacuo, the residue was treated with 25 mL of 1N hydrochloric acid and the solvent was removed again. The product is purified by silica gel column chromatography eluting with a mixture of ethyl acetate, ethanol, aqueous ammonium hydroxide solution and water in a ratio of 20: 10: 1: 1, and then 15: 10: 1: 1 to give a gum which is left to leave.

4 9 • 9 9 • 4 9 9

9 9 9 ·

crystallize from a very small amount of water, and then filter to give the product (7-9) as a white solid.

¹ H NMR (300 MHz, CD 3 OD): d 1.75-2.1 (4H, m), 2.55-3.1 (8H, m), 3.28 (1H, q), 3.3 ( 1H, m), 3.4-3.55 (3H, m), 3.63 (1H, q), 3.85 (3H, s), 5.47 (1H, dd), 6.55 (1H d), 6.80 (1H, d), 7.48 (1H, d), 7.68 (1H, d), 8.09 (1H, d).

Another aspect of the invention is the R-enantiomer and 3 (R) - (6-methoxy-pyridin-3-yl) -3- {2-oxo-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2), respectively. -yl) -propyl] -imidazolidin-1-yl} -propionic acid, which is accomplished by substituting N-benzyl- (S) -α-methylbenzylamine for N-benzyl- (R) -amethylbenzylamine during the preparation of intermediate (7-4) .

Another object of the invention is the racemate and 3- (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridine-2-), respectively. yl) -propyl] -imidazolidin-1-yl} -propionic acid, which is prepared by substituting racemic N-benzyl-α-methylbenzylamine for N-benzyl- (R) -amethylbenzylamine during the preparation of intermediate (7-4).

5-Bromo-2-ethoxypyridine (8-2)

To 200 ml of ethanol was added 4.87 g (0.212 mol) of sodium metal and the mixture was stirred until complete dissolution. To this solution was added 10 g (0.0424 mol) of 2,5-dibromopyridine (Alcfrich), and the resulting mixture was stirred at reflux temperature for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. After extraction twice with ethyl acetate, the organic portion was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give the product (8-2) as a red-brown solid which was used in the next synthesis without further purification.

¹ H NMR (300 MHz, CDCl 3): d 1.4 (3H, t), 4.33 (2H, q), 6.63 (1H, d),

7.62 (1 H, dd), 8.19 (1 H, d).

3 (S) - (6-Ethoxy-pyridin-3-yl) -3-afanine ethyl ester (8-3)

The resulting product (8-3) is prepared using the product (8-2) according to the synthesis procedure of intermediate (7-5).

¹ H NMR (300 MHz, CDCl 3): d 1.25 (3H, t), 1.39 (3H, t), 2.61 (1H, dd), 2.67 (1H, dd), 4.15 (2H, q), 4.34 (2H, q), 4.40 (1H, dd), 6.71 (1H, d),

7.62 (1H, dd); 8.11 (1H, d).

3 (S) - (6-Ethoxy-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl -imidazolidin-1-yl} -propionic acid (8-4)

The resulting product (8-4) was prepared using intermediates (2-9A) and (8-3) according to the procedure described in Scheme 2.

¹ H NMR (300 MHz, CD 3 OD): d 1.37 (3H, t), 1.8-2.0 (4H, m), 2.65 (2H,

t), 2.82 (2H, t), 2.95-3.10 (2H, m), 3.15 (2H, m), 3.23 (2H, dt), 3.46 (2H, m) 3.51 (2H, t), 4.32 (2H, q), 5.41 (1H, t), 6.62 (1H, d), 6.84 (1H, t,

d), 7.57 (1H, d), 7.76 (1H, dd), 8.13 (1H, d).

• · »

Scheme 9

ru tert-butyl acrylate

Pd (OAc) ₂ , (o-Toyl) _and P 110 ° C, CH 2 CN

CO ₂ tBu 9 9 9

N

Li .Bn

THF, -78 ° C

a) Pd / C, 78 ° C, AcOH 1,4-cyclohexadiene

b) HCl, EtOH n ₂

N

2HCl ₁ H ₂ N

9-4

NH ₂

O

Λν ^Λ - / ^{: 0} = ^Η \ _I

3- (6-Amino-pyridin-3-yl) -acrylic acid tert-butyl ester (9-2)

A mixture of 10 g (58 mmol) of 2-amino-5-bromo-pyridine (9-1), 50 ml (344 mmol) of tert-butyl acrylate, 50 ml (359 mmol) of triethylamine, 3.0 g (9.8 mmol) of tri-o-tolylphosphine and 1.0 g (4.5 mmol) of palladium (II) acetate in 150 ml of methyl cyanide are bubbled with argon for 5 minutes, followed by 20 min.

reflux at 110 ° C. The reaction mixture was cooled and concentrated. The resulting residue was purified by silica gel flash column chromatography eluting with 1: 1 ethyl acetate: hexanes to give the desired product (9-2) as a solid.

Rf (silica, ethyl acetate / hexanes 1: 1) = 0.26 3 (S) - (6-amino-pyridin-3-yl) -3- [benzyl- (1 (R) -) - tert -butyl ester phenylethyl) amino] propionic acid (9-3)

To a solution cooled to 0 ° C, 4.0 g (19 mmol) of (R) - (+) - N -benzyl-α-methylbenzylamine in 50 ml of tetrahydrofuran was added portionwise over 5 minutes, 11.3 mi (28.2 mmol) was added. Of 2.5 M n-butyllithium solution. The reaction mixture was stirred at 0 ° C for 30 minutes and cooled to -78 ° C. A solution of 2.0 g (9.4 mmol) of the product (92) in 20 mL of tetrahydrofuran was gradually added and the reaction mixture was stirred at -78 ° C for 40 min. After treatment with saturated ammonium chloride solution at -78 ° C, the mixture was allowed to warm to room temperature and then extracted three times with ethyl acetate. The combined organics were washed with saturated sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / hexanes (1: 2) to give the desired product (9-3) as an oil.

Rf (silica, ethyl acetate: 1: 1 hexanes) = 0.28 3 (S) -amino-3- (6-amino-pyridin-3-yl) -propionic acid ethyl ester dihydrochloride (9-4)

A mixture of 0.5 g (1.2 mmol) of the resulting product (9-3) and 0.4 g of a 10% palladium on charcoal solution in 10 ml of acetic acid was bubbled with argon for 5 minutes and then heated to 78 °. C.

Ml2.ΪContinuously, 2 ml (21.1 mmol) of 1,4-cyclohexadiene was added and the reaction mixture was stirred for 3 hours. After filtration through celite, the solution was concentrated and the residue purified by flash chromatography on silica gel eluting with 1: 1: 0.04 ethyl acetate: methanol: ammonium hydroxide to give the product as an oil. Hydrogen chloride gas was bubbled through a mixture of 1.2 g of this oil in 20 ml of ethanol for 10 minutes. The reaction mixture is stirred for 24 hours and then concentrated to give the desired product (9-4) as the hydrochloride salt.

¹ H NMR (400 MHz, CD 3 OD): d 8.11 (d, J = 9.6 Hz, 1H), 8.08 (s, 1H), 7.13 (d, J = 9.6 Hz, 1H) ), 4.77 (m, 1H), 4.18 (q, J = 6.8 Hz, 2H), 3.22-3.02 (m, 2H), 1.24 (t, J = 6, 8 Hz, 3H).

3 (S) - (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} -propionic acid (9-5)

The resulting product (9-5) was prepared as the trifluoride salt according to the procedure of Scheme 2 and using intermediates (2-9A) and (9-4).

1 H NMR (300 MHz, CD 3 OD): d 7.90 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.7, 2.1 Hz, 1H), 7.03 ( d, J = 8.7 Hz, 1H), 6.47 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H), 5.38-5, 30 (m, 1H), 3.40-3.37 (m, 2H), 3.263.16 (m, 4H), 3.03-2.86 (m, 2H), 2.70-2.66 ( m, 2H), 2.55-2.50 (m, 2H), 2.14-2.02 (m, 2H), 1.93-1.79 (m, 4H).

Scheme 10

426

salt with NaHCO 3 / CHCl 3

10-7

10-6 • 00

0 · ·

/ 1/00 00

Scheme 10 (2nd part)

Pd (OH) ₂ / H ₂

10-7 -MeOH / AcOH

H ₂ O

HsN ^

CO ₂ Et

10-8

ethyl 3- (3-hydroxy-4-nitrophenyl) -acrylic acid ethyl ester (10-2)

To a stirred solution of 20.28 g (132.5 mmol) of aldehyde (10-1) in 400 mL of methylene chloride was added 46.12 g (132.5 mmol) of (carbethoxymethylene) triphenylphosphorane at room temperature over 10 minutes. The resulting orange solution was stirred at room temperature for 2 hours. The solution was concentrated to one-fourth its volume and the product was purified by silica gel flash column chromatography eluting with 30:70 ethyl acetate: hexanes to give the title product (10-2) as a bright yellow solid.

TLC Rf = 0.75 (25:75 ethyl acetate / hexanes)

42 / • 4

1 H NMR (300 MHz, CDCl 3): d 8, (1.4] (d, 1H), 7.60 (d, 1H), 7.15 (dd, 1H), 6.54 (d, 1H), 4.30 (q, 2H); 1.36 (t, 3H).

ethyl 3- (4-amino-3-hydroxy-phenyl) -acrylic acid ethyl ester (10-3)

To a stirred suspension of the title product (10-2) (4.64 g, 19.6 mmol), ammonium chloride (524 mg, 9.8 mmol), ethanol (140 mL) and water (70 mL) was added 2.72 g (48.9 mmol). ) of powdered iron. The resulting yellow suspension was heated under reflux for 1.5 hours, and then the hot solution was filtered through celite. The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated sodium chloride solution. The aliquots were separated, the ethyl acetate portion was dried over sodium sulfate and concentrated to give intermediate (10-3), which was used in the next synthesis without further purification.

TLC Rf = 0.2 (25:75 ethyl acetate / hexanes)

1 H NMR (300 MHz, CDCl 3): d 7.57 (d, 1H), 7.00 (m, 2H), 6.68 (d, 1H), 6.20 (d, 1H), 4.26 ( q, 2H), 4.10 (bs, 2H), 1.33 (t, 3H).

3- [4- (2-chloroacetylamino) -3-hydroxy-phenyl] -acrylic acid ethyl ester (10-4)

To a stirred solution of intermediate (10-3) (3.38 g, 16.3 mmol) in chloroform (80 mL) was added saturated sodium bicarbonate (50 mL), followed by cooling to 0 ° C. A solution of 1.94 ml (24.4 mmol) of chloroacetyl chloride in 30 ml of chloroform was added dropwise to the cooled mixture of two phases. After addition was complete, the reaction was stirred at 0 ° C for 1 h and the fractions were separated. The aqueous portion was extracted twice with ethyl acetate. The combined organics were washed with saturated brine, dried over sulfate

The product was concentrated to give the product (10-4) which was used in the next synthesis without further purification.

TLC Rf = 0.4 (25:75 ethyl acetate in hexanes)

1 H NMR (300 MHz, CDCl 3): d 10.33 (s, 1H), 9.58 (s, 1H), 8.02 (d, 1H), 7.51 (d, 1H), 7.19 ( d, 1H), 7.12 (s, 1H), 6.39 (d, 1H), 4.42 (s, 2H),

4.17 (q, 2H); 1.25 (t, 3H).

3- (3-Oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) acrylic acid ethyl ester (10-5)

To a stirred solution of 4.28 g (15.0 mmol) of product (10-4) in 50 mL of dimethylformamide was added 4.50 g (32.6 mmol) of potassium carbonate. The resulting suspension was heated at 50 ° C for 12 hours, the mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. After extraction twice with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The product was purified by flash silica gel column chromatography eluting with 25:75 ethyl acetate: hexanes to give intermediate (10-5) as a beige solid.

TLC Rf = 0.5 (25:75 ethyl acetate: hexanes).

1 H NMR (300 MHz, CDCl 3): d 10.91 (s, 1H), 7.54 (d, 1H), 7.37 (s, 1H), 7.31 (d, 1H), 6.90 (s) d, 1H), 6.51 (d, 1H), 4.60 (s, 2H), 4.16 (q, 2H), 1.24 (t, 3H).

3 (R) - [Benzyl- (1-phenylethyl) amino] -3- (S) - (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) ethyl ester propionic (10-6)

To a stirred solution of 5.43 g (25.7 mmol) of (R) - (+) - N-benzyl-α-methylbenzylamine and 75 ml of anhydrous tetrahydrofuran was added at 0 ° C.

Κ3ΰ

4444 4 4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 4 4

4.4 ml (25.7 mmol) of 2.5 M butyllithium in hexanes was added via syringe. The violet-red solution was stirred at 0 ° C for 15 minutes and then cooled to -78 ° C. After addition of a solution of 2.12 g (8.6 mmol) of intermediate (10-5) in 50 ml of anhydrous tetrahydrofuran by syringe, the resulting brown solution was stirred at -78 ° C for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, then allowed to warm to room temperature and extracted twice with diethyl ether. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The product was purified by flash chromatography on silica gel, eluting with a gradient of from 15:85 to 25:75 ethyl acetate / hexanes to give the title intermediate (10-6) as a white foam.

TLC Rf = 0.25 (25:75 ethyl acetate: hexanes)

1 H NMR (300 MHz, CDCl 3): d 10.89 (s, 1H), 7.32 (m, 10H), 7.10 (m, 2H), 6.91 (d, 1H), 4.62 ( s, 2H), 4.39 (m, 1H), 4.13 (q, 2H), 3.96 (m, 1H), 3.68 (s, 2H), 2.56 (m, 2H), 1 28 (m, 6H).

3 (R) - [Benzyl- (1-phenylethyl) -amino] -3- (S) - (4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) ethyl ester ) propionic acids (10-7)

To a stirred suspension of a 60% solution of 65 mg (1.6 mmol) of sodium hydride in 5 mL of dimethylformamide was added a solution of intermediate (10-6) in 10 mL of dimethylformamide under argon under a syringe. The yellow solution was stirred at room temperature for 30 minutes, and then 0.5 mL (8.0 mmol) of iodomethane was added. The reaction solution was stirred at room temperature for an additional 30 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The aqueous portion was extracted three times with methylene chloride. The combined organics were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. Flash chromatography on silica gel, silica gel, flash chromatography. eluting with a 25:75 mixture of ethyl acetate and hexanes gave intermediate (10-7) as a clear oil.

TLC Rf = 0.6 (25:75 ethyl acetate / hexanes)

1 H NMR (300 MHz, CDCl 3): d 7.30 (m, 10H), 7.06 (m, 2H), 6.91 (d, 1H), 4.62 (s, 2H), 4.39 (m, 1H), 4.13 (q, 2H), 3.96 (m, 1H), 3.68 (s, 2H), 3.35 (s, 3H), 2.56 (m, 2H), 1.26 (m, 6H).

3 (S) -Amino-3- (4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -propionic acid ethyl ester (10-8)

The stirred solution of intermediate (10-7) (581 mg, 1.2 mmol), methanol (10 ml), acetic acid (1.0 ml) and water (0.3 ml) was degassed in the presence of argon over 5 minutes. After addition of 581 mg of palladium hydroxide, the reaction mixture was placed under an atmosphere of hydrogen at 50 psi for 2.5 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated to give intermediate (10-8) as a clear oil.

TLC Rf f 0.3 (5:95 methanol: methylene chloride)

1 H NMR (300 MHz, CDCl 3): d 7.04 (m, 2H), 6.93 (dd, 1H), 4.61 (s, 2H), 4.39 (m, 1H), 4.13 ( q, 2H), 3.37 (b, 2H), 3.35 (s, 3H), 2.69 (m, 2H), 1.24 (t, 3H).

3 (S) - (4-Methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- {2-oxo-3- [3-5,6] 7,8-Tetrahydro- [1,8] naphthyridin-2-yl) propyl] -imidazolidin-1-yl} -propionic acid (10-9)

The resulting product (10-9) was prepared using intermediates (2-9A) and (10-8) according to the procedure described in Scheme 2.

1 H NMR (400 MHz, d 6 -DMSO): d 7.83 (bs, 1H), 7.60 (d, 1H), 7.11 (d,

1H), 6.99 (d, 1H), 6.93 (s, 1H), 6.63 (d, 1H), 5.20 (t, 1H), 4.64 (s, 2H),

3.3-2.8 (m, 10H), 3.25 (s, 3H), 2.72 (m, 2H), 2.59 (m, 2H), 1.81 (m,

2H), 1.74 (m, 2H).

Scheme 11

4,449 4

9 9

4 4

4 4 9

94

4 9 4

4 4 4

4 4 4

4 4 4 ·· 44

ethyl acrylate

Pd (OAc) ₂ , (o-Tolyl) 3 P 110 ° C, CH 3 CN

Pd (OH) ₂ / C, H ₂ AcOH / EtOH

11-7 • · · · · · · · · 99 · · 999 999 • φ · · ·

2-tert-butoxycarbonylamino-5-aminopyridine (11-2)

A solution of 10.1 g (58.4 mmol) of 2-amino-4-bromopyridine (11-1) in 150 mL of molten t-butanol was treated with 14.0 g (64.2 mmol) of di-tert-butyl dicarbonate. After stirring for 12 hours, the solvent was evaporated and the residue was purified by flash column chromatography on silica gel eluting with 5: 1 chloroform: hexanes to give the product (11-2) as a solid.

Rf (silica, 100% chloroform) = 0.56.

¹ H NMR (300 MHz, CDCl 3): d 8.82 (bs, 1H), 8.38 (d, 1H), 8.78 (d, 1H), 7.78 (dd, 1H), 1.55 (s, 9H).

2- (tert-butoxycarbonyl-methyl-amino) -5-amino-pyridine (11-3)

Sodium hydride was added portionwise at 0 ° C to a solution of 6.0 g (22.0 mmol) of the product (II-2) in 50 mL of dimethylformamide. After stirring for 40 minutes, 3.4 g (24.0 mmol) of methyl iodide are added in one portion. The reaction mixture was stirred for 5 hours, water (300 ml) was added and the mixture was extracted three times with ethyl ether. 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 with 6: 1 chloroform: hexanes to give the desired product (11-3) as a solid.

Rf (silica, 100% chloroform) = 0.40.

¹ H NMR (300 MHz, CDCl 3): d 8.40 (dd, 1H), 7.68 (m, 2H), 3.36 (s, 3H), 1.55 (s, 9H).

9 000 000 0 0 0 0 0 0 0

00 • 0 0 0 «0 · · · 0 0

00 3- [6- (tert-butoxycarbonyl-methylamino) -pyridin-3-yl] -acrylic acid ethyl ester (11-4)

A mixture of intermediate (11-3) (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 62.7 mmol), triethylamine (17 mL, 125.5 mmol), 1.3 g (6.2 mmol). of trietolylphosphine and 0.5 g (2.1 mmol) of palladium (II) acetate in 50 ml of methyl cyanide are purged with argon for 5 minutes and then heated at reflux at 110 ° C for 20 hours. The reaction mixture was cooled and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / hexanes (1: 3) to give the desired intermediate (11-4) as an oil.

¹ H NMR (300 MHz, CDCl 3): d 8.47 (bs, 1H), 7.82 (m, 2H), 7.64 (d, 1H), 6.42 (d, 1H), 4.27 (q, 2H), 3.43 (s, 3H), 1.54 (s, 9H), 1.34 (t, 3H).

3-Benzylamino-3- [6- (tert-butoxy-carbonyl-methyl-amino) -pyridin-5-yl] -propionic acid ethyl ester (11-5)

A mixture of intermediate (11-4) (1.7 g, 5.6 mmol) and benzylamine (8 mL, 73.2 mmol) was heated in a sealed tube at 95 ° C for 24 h. The crude reaction mixture was purified by flash silica gel column chromatography eluting with a 1: 3 to 1: 1 mixture of ethyl acetate and hexanes to give the desired product (11-5) as an oil.

Rf (silica, 1: 1 ethyl acetate / hexanes) = 0.63.

3-Amino-3- [6- (tert-butoxycarbonylmethyl-amino) -pyridin-3-yl] -propionic acid ethyl ester (11-6)

A mixture of intermediate (11-5) (1.5 g, 3.6 mmol), 20% palladium hydroxide on charcoal (0.3 g), acetic acid (5.5 ml) and ethanol (50 ml) was bubbled with argon under vacuum three times. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours and then filtered through celite. Removal of the solvent gave the resulting intermediate (11-6) as an acetate salt.

1 H NMR (300 MHz, CDCl 3): d 8.38 (d, 1H), 7.70 (m, 2H), 4.50 (dd, 1H), 4.15 (q, 2H), 3.40 ( s, 3H), 2.80 (m, 2H), 1.25 (t, 3H).

3- (6-methylamino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl] - imidazolidin-1-yl} propionic acid (11-7)

The resulting product (11-7) was prepared as the trifluoroacetic acid salt using intermediates (2-9A) and (11-6) according to the procedure described in Scheme 2.

1 H NMR (300 MHz, CD 3 OD): d 7.92 (dd, J = 9.6, 1.6 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.57 ( d, J = 7.6 Hz, 1H), 7.03 (d, J = 9.6 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 5.28 (m, 1H), 3.51-3.36 (m, 5H), 3.28-3.17 (m, 3H), 3.05 (m, 2H), 3.02 (s, 3H), 2.82 (m, 2H), 2.67 (m, 2H), 1.98-1.84 (m, 4H).

Scheme 12

3- (2-Fluoro-biphenyl-4-yl) -acrylic acid ethyl ester (12-2)

A solution of 7.5 g (31.8 mmol) of 2-fluoro-4-bromobiphenyl (12-1), 4.3 ml of ethyl acrylate, 0.714 g (3.2 mmol) of palladium acetate, 1.94 g ( (5 mmol) of tri-o-tolylphosphine and 12 ml of triethylamine in a sealed tube for 12 hours

heated to 100 ° C. The reaction mixture was cooled to room temperature and diluted with 40 mL of dichloromethane. The organic solution was washed with 20 mL of 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and 20 mL saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography eluting with 95: 5 to 90:10 hexanes / ethyl acetate to give the acrylate ester (12-2) as a white solid.

TLC Rf = 0.44 (10% ethyl acetate in hexanes).

3- [benzyl- (1 (R) -phenylethyl) -amino] -3- (2-fluoro-biphenyl-4-yl) -propionic acid ethyl ester (12-3)

The solution cooled to 0 ° C, 8.9 mL (42.6 mmol) of (R) - (+) - N-benzyl-α-methyl-benzylamine in 100 mL of tetrahydrofuran was treated with 26.6 mL (42.6 mmol) A 1.6 M solution of n-butyllithium in a mixture of hexanes. After stirring for 10 minutes, the violet solution was cooled to -78 ° C. The solution was treated with a solution of 5.72 g (21.3 mmol) of the ester (12-2) in 10 mL of tetrahydrofuran. After stirring for 20 minutes, the reaction was quenched by the addition of 5 mL of saturated aqueous ammonium chloride solution and the cooling bath was removed. The reaction mixture was diluted with 100 mL of diethyl ether and washed with 50 mL of 10% aqueous citric acid, 50 mL of saturated aqueous sodium bicarbonate, 30 mL of 5% aqueous acetic acid, 50 mL of 10% aqueous potassium carbonate, and 50 mL of saturated chloride solution sodium. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with hexanes / ethyl acetate (90:10) to give intermediate (12-3).

TLC Rf = 0.48 (10% ethyl acetate in hexanes).

3-Amino-3- (2-fluoro-biphenyl-4-yl) -propionic acid ethyl ester (12-4)

A solution of 5.65 g (11.75 mmol) of dibenzylamine (12-3) in a mixture of 90 ml of ethanol and 10 ml of acetic acid is bubbled with argon and treated with 3 g of palladium hydroxide under a hydrogen pressure of 1 bar for 12 hours. . An additional 2.5 g of palladium hydroxide was added after 24, 48 and 144 hours. Argon was bubbled through the reaction mixture, filtered through celite, and the filtrate was dissolved in aqueous hydrochloric acid (pH = 1). The aqueous solution was washed with ethyl acetate, neutralized with saturated aqueous sodium bicarbonate solution and extracted three times with 30 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired product (12-4).

¹ H NMR (300 MHz, CD 3 OD): δ 7.41 (m, 8H), 4.10 (m, 1H), 4.06 (m, 2H), 2.73 (m, 2H), 1.18 (m, 3H) ppm.

3 (S) - (2-Fluoro-biphenyl-4-yl) -3- {2-oxo- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} propionic acid (12-5)

The resulting product (12-5) was prepared using intermediates (2-9A) and (12-4) according to the procedure described in Scheme 2.

¹ H NMR (300 MHz, CD 3 OD): δ 7.49 (m, 9H), 6.64 (d, J = 7.3 Hz, 1H), 5.49 (m, 1H), 3.31 (m 9H), 2.83 (m, 2H), 2.74 (m, 2H), 1.97 (m, 4H) ppm.

• · · · · ·

Diagram 13 ^Et0 \

Ph ₃ P = /

* ·

CHO

13-1

1 ^ 4

1.

Me

H n-BuLi 'Ph

Second Pd (OH) _2, H ₂ (g)

J / Sl · · * ·· ♦> ♦ ·

Mff 3- (3-hydroxy-4) ethyl ester Mff -nitro-phenyl) -acrylic (13-2)

To a solution of 15.0 g (98.0 mmol) of aldehyde (13-1) 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 paste formed was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate in methylene chloride to afford intermediate (13-2) 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 = 7.2 Hz, 2H), 1.32 (t, J = 6.9 Hz, 3H) ppm.

3- (2-Oxo-2,3-dihydro-benzoxazol-6-yl) -acrylic acid ethyl ester (13-3)

To a solution of 12.0 g (57.4 mmol) of nitrophenol (13-2) in 200 mL of 70 ° C acetic acid / water 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 filter cake was washed twice with 200 mL of ethyl acetate. The filtrate was carefully neutralized three times with 100 ml of saturated aqueous sodium bicarbonate solution. 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 of an orange solid in 81% yield.

An aliquot of 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 and stirred at room temperature for 24 hours.

• ·

The solution was diluted with 100 mL of ethyl acetate and washed with 50 mL of 10% hydrochloric acid and 50 mL of saturated sodium chloride solution. 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 afford intermediate (13-3) 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, 1H), 7.09 (d, J = 8.1Hz, 1H), 6.47 (d, J = 15.9Hz, 1H), 4.22 (q, J = 7.2Hz, 2H) , 1.31 (t, J = 7.2Hz, 3H) ppm.

3 (S) -Amino-3- (2-oxo-2,3-dihydro-benzoxazol-6-yl) -propionic acid ethyl ester (13-4)

A solution of 4.08 g (19.3 mmol) of (R) - (+) - N-benzyl-α-methylbenzylamine in 120 ml of tetrahydrofuran at 0 ° C is treated with 7.72 ml of a 2.5 M solution of n-butyl- lithium in 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 (13-3) in 20 ml of tetrahydrofuran, the mixture was stirred for 15 minutes at -78 ° C, followed by the addition of 25 ml of saturated aqueous ammonium chloride solution and cooling bath. removes. The reaction mixture was allowed to warm 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 β-aminoester as a yellow oil. The amino ester is dissolved in a mixture of 54 ml of ethanol, 4.8 ml of water and 1.2 ml of acetic acid, the solution is degassed in the presence of argon and treated with 2.74 g of palladium hydroxide. The reaction mixture was placed under an atmosphere of hydrogen at 50 psi hydrogen. After 18 hours, the reaction • 9 · 9 · ·

MZ.

the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated to give the resulting ester (13-4) as an off-white solid.

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

1 H NMR (300 MHz, CD 3 OD): δ 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 (m, 2H) t, J = 7.2 Hz, 3H) ppm.

3 (S) - (2-Oxo-2,3-dihydro-benzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid (13-5)

The resulting product (13-5) was prepared using intermediates (2-9A) and (13-4) according to the procedure described in Scheme 2.

¹ H NMR (300 MHz, CD 3 OD); δ 7.57 (d, J = 7.3 Hz, 1H), 7.28 (s, 1H),

7.19 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 5.47 (m, 1H), 3.30 (m, 9H), 2.82 (m, 2H), 2.66 (m, 2H), 1.96 (m, 6H) ppm.

443

Scheme 14

14-:

Bn

14-4

14-6

9 · 93 4 1

9 «· *

9 * 4 <

► · · <

»· · <

t · · «

4 9 9 3- (4-Hydroxy-3-fluorophenyl) -acrylic acid ethyl ester (14-2)

A solution of 50 g (261.8 mmol) of 2-fluoro-4-bromophenol (14-1), 34 ml of ethyl acrylate, 2.5 g of palladium acetate, 5 g of tri-o-tolyiphosphine and 83 ml of triethylamine is heated to 100 ° C in a sealed tube. The reaction was cooled to room temperature and diluted with 100 mL of dichloromethane. The organic solution was washed with 40 mL of 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and 40 mL of saturated sodium chloride. The organic solution was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with a gradient of 50:50 hexanes: ethyl acetate to 100% ethyl acetate to give acrylic acid (14-2) as a white solid.

TLC Rf = 0.45 (50% ethyl acetate in hexanes).

3- [benzyl- (1 (R) -phenylethyl) amino] -3- (4-ethoxy-3-fluorophenyl) propionic acid ethyl ester (14-4)

To a stirred solution of intermediate (14-2) (49.25 g, 234.5 mmol) in dimethylformamide (600 mL) was added cesium carbonate (84.1 g, 257.9 mmol) and ethyl iodide (18.8 mL, 234.5 mmol). After stirring at room temperature for 12 hours, the reaction mixture is diluted with 1 L of ethyl acetate and washed six times with 300 ml of water, once with 200 ml of 10% aqueous citric acid solution, once with 200 ml of saturated aqueous sodium bicarbonate solution and once with 300 ml of saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give 52.9 g (95% yield) of product (14-3) as an orange oil which crystallized on standing.

A cooled solution of 71 ml (339.4 mmol) of (R) - (+) - N-benzyl-t-methylbenzylamine in 650 ml of tetrahydrofuran at 0 ° C was treated with *

solution of 212 ml (339.4 mmol) of a 1.6 M solution of n-butyllithium in a mixture of hexanes. After stirring for 10 minutes, the violet solution was cooled to -78 ° C and the solution was treated with a solution of 53.8 g (226.3 mmol) of ester (143) in 100 mL of tetrahydrofuran. After stirring for 20 minutes, the reaction is quenched by addition of 50 ml of saturated aqueous ammonium chloride solution and the cooling bath is removed. The reaction mixture was diluted with 1000 mL of diethyl ether and washed with 300 mL of 10% aqueous citric acid, 300 mL of saturated aqueous sodium bicarbonate, 300 mL of 5% aqueous acetic acid, 300 mL of 10% aqueous potassium carbonate, and 200 mL of saturated chloride solution sodium. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with hexanes / ethyl acetate (85:15) to give the title intermediate (14-4).

TLC Rf = 0.39 (25% ethyl acetate in hexanes).

3-Amino-3- (4-ethoxy-3-fluorophenyl) propionic acid ethyl ester (14-5)

A solution of dibenzylamine (14-4) (30.0 g, 66.8 mmol) in ethanol (340 ml) and acetic acid (30 ml) was bubbled with argon and treated with palladium hydroxide (6 g) and placed under hydrogen atmosphere under pressure for 12 hours. of hydrogen 0.1 MPa. After 24 and 48 hours, 2.5 g of palladium hydroxide were added at a further portion. Argon was bubbled through the reaction mixture, filtered through celite and the filtrate collected. The filtrate is concentrated to give the desired amine (14-5).

1 H NMR (300 MHz, CD 3 OD): δ 7.19 (m, 3H), 4.62 (m, 1H), 4.07 (m, 4H), 2.99 (m, 2H), 1.39 ( m, 3H) 1.18 (m, 3H) ppm.

440

3 (S) - (4-Ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) - propyl] -imidazolidin-1-yl] propionic acid (14-6)

The resulting product (14-6) was prepared using intermediates (2-9A) and (14-5) according to the procedure described in Scheme 2.

1 H NMR (300 MHz, CD 3 OD): d 7.45 (d, J = 7.3 Hz, 1H), 7.04 (m, 3H), 6.53 (d, J = 7.3 Hz, 1H) 5.43 (m, 1H); 4.06 (q, J = 7.0 Hz, 2H); 3.48 (m, 6H); 3.15 (m, 1H); 2.78 (m, 1H); 6H), 2.55 (m, 2H), 1.96 (m, 3H), 1.38 (t, J = 7.0 Hz, 3H) ppm.

Scheme 15

φφ · ♦ · · ♦ φ · · φ φ · φ · φ φφφ ·· ♦ ·

Scheme 15 (2nd part)

¹ H NMR (300 MHz, CD 3 OD): δ 8.13 (m, 2Η), 7.48 (d, 1H, J = 7 Hz), 7.35 (s, 1H), 6.55 (d, J = 8 Hz, 1H, 5.53 (m, 1H), 4.13 (q, 2H, 7Hz), 3.313.70 (m, 7H), 3.06 (m, 2H), 2.55 -2 .85 (m, 6H), 1.88-2.15 (m, 5H), 1.42 (t, 3H, J = 7 Hz).

4 4 4 4 · 4

W:

44

4 4 4 • 4 4

Scheme 16

AlCl ₃₎ EtSH

NaOH

16-5 R = H ······ 3 (S) -Amino-3- (5-methoxy-pyridin-3-yl) -propionic acid tert-butyl ester (16-2)

3-bromo-5-methoxy-pyridine (16-1), the preparation of which is described in J. Org. Chem., 1990, 55, 69, is converted to (16-2) according to the procedure for converting intermediate (1-4) to product (1-6).

¹ H NMR (300 MHz, CD 3 OD): δ 8.20 (d, 1H, J = 3 Hz), 8.18 (d, 1H, J = 2 Hz), 7.50 (s, 1H,), 4.51 (m, 1H), 3.90 (s, 3H), 2.87 (m, 2H), 1.37 (m, 9H).

3 (S) - (5-Methoxy-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-) - ethyl ester yl) propyl] -imidazolidin-1-yl} -propionic (16-3)

The resulting compound (16-3) was prepared using intermediates (2-9A) and (16-2) according to the procedure described in Scheme 2.

TLC Rf = 0.27 (silica, chloroform, ethyl acetate, methanol = 70:20:10).

¹ H NMR (300 MHz, CDCl 3): δ 8.23 (d, 1H, J = 3Hz), 8.15 (s, 1H), 7.22 (s, 1H), 7.02 (d, 1H, J = 7Hz), 6.33 (d, 1H, 7Hz), 5.46 (t, 1H, J = 8Hz), 4.78 (s, 1H), 4.11 (m, 2H), 3.84 (s, 3H), 3.30 (m, 6H), 3.00 (m, 2H), 2.67 (t, 2H, J = 6 Hz), 2.52 (m, 2H), 1.85 ( m, 6H), 1.23 (m, 3H).

3 (S) - (5-Hydroxy-pyridin-3-yl) -3- {2-oxo-3- (3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-) -) yl) propyl (1-imidazolidin-1-yl) -propionic (16-4)

To a stirred solution of 200 mg (0.4278 mmol) of intermediate (16-3) a

0.5 ml of ethanethiol and 3 ml of methylene chloride were added 570 mg (4.28 mmol) of aluminum chloride. After 1.0 h, the reaction was quenched by addition of saturated sodium bicarbonate solution. After addition of ethyl acetate, argon was bubbled through the reaction mixture for 1.0 hour. The organic portion was separated, washed with saturated brine, dried over magnesium sulfate, and then concentrated to give the resulting phenol (16-4) as a yellow oil.

TLC Rf = 0.22 (silica; chloroform, ethyl acetate, methanol = 70:20:10).

3 (S) - (5-Hydroxy-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)] propyl] -imidazolidin-1-yl} propionic acid (16-5)

The resulting product (16-5) is prepared using intermediate (16-4) by basic hydrolysis according to the procedure described in Scheme 2.

TLC Rf = 0.39 (silica; ethanol, water, ammonium hydroxide = 10: 1: 1).

¹ H NMR (300 MHz, CD 3 OD): δ 8.01 (m, 2H), 7.46 (d, 1H, J = 7Hz), 7.20 (s, 1H), 6.53 (d, J = 8 Hz, 1H, 5.49 (m, 1H), 3.51-3.68 (m, 2H), 3.46 (t, 2H, 5Hz), 3.19 (m, 2H), 3 1.00 (m, 2H), 2.52-2.78 (m, 6H), 1.92 (m, 4H).

Scheme 17

17-1

17-2 · * 9999

3 (S) - (ethynyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) propyl] -imidazolidin-1 -yl} -propionic acid (17-2)

9 99 99 99

999 9 9 9999

99 9 99999 9 • ·· ·· · ^f * · * 99 99999999 * · ··

The resulting product (17-2) was prepared using intermediates (2-9A) and (17-1), the preparation of which was described by J.A. Zablocki et al. in J. Med. Chem, 1995, 38, 2378-2394 according to the procedure described in Scheme 2.

TLC Rf = 0.32 (silica, 15: 10: 1: 1 = ethyl acetate, ethanol, water, ammonium hydroxide).

¹ H NMR (300 MHz, CD 3 OD): δ 7.45 (d, J = 7 Hz, 1H), 6.53 (d, J = 8 Hz, 1H), 5.15 (m, 1H), 3.31 -3.70 (m, 7H), 2.55-2.85 (m, 7H), 2.35 (m, 1H), 1.88-2.15 (m, 4H).

Scheme 18

2 (S) -Benzenesulfonyl-amino-3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine- 1-yl} -propionic acid (18-2)

The resulting product (18-2) was prepared using intermediates (2-9A) and (18-2) (the preparation of which is described in Scheme A, substituting 4-iodophenylsulfonyl chloride for phenylsulfonyl chloride according to the procedure described in Scheme 2). .

45Z

TLC Rf = 0.23 (silica, ammonium hydroxide).

1 H NMR (300 MHz, CD 3 OD): δ

15: 10: 1: 1 = ethyl acetate, ethanol, water,

7.81 (m, 2H), 7.36 (m, 3H), 7.10 (d,

1H, J = 8Hz), 6.37 (d, 1H, J = 7Hz), 3.61 (m, 1H,> 3.36 (m, 2H), 3.02 3.18 (m, 6H) 3.00 (m, 2H), 2.68 (t, 2H, J = 6 Hz), 2.50 (m, 2H), 1.79 1.90 (m, 4H).

Scheme 19

ethyl 3-amino-pent-4-enoate (19-1)

A mixture of 0.025 g of a 5% palladium solution on barium sulfate and 0.30 ml of quinoline was stirred for 30 minutes under a hydrogen atmosphere. After addition of 1.77 g (10.0 mmol) of 3-amino-pent-4-ynoic acid ethyl ester (17-1) in 15 ml of ethanol, the solution was stirred for an additional 2.5 hours. The solution is filtered through celite and <9 9 9 9 9

Concentrate in vacuo to give 2.65 g of crude product (191).

1 H NMR (CDCl 3, 300 MHz): δ 8.40-7.60 (br s, 2H), 6.11-5.96 (m, 1H), 5.585.53 (d, 1H), 5.44-5, 41 (d, 1H), 4.31-4.16 (m, 3H), 3.12-2.86 (m, 2H), 1,291.25 t, 3H).

3 (S) - {2-Oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent-4 -enoic acid (19-2)

The resulting product (19-2) was prepared using intermediates (2-9A) and (19-1) according to the procedure described in Scheme 2.

¹ H NMR (CDCl 3, 300 MHz): δ 11.1 (s, 1H), 7.21-7.19 (d, 1H), 6,266.23 (d, 1H), 5.91-5.78 ( m, 1H), 5.22-5.00 (m, 3H), 3.79-3.16 (m,

H, 2.77-2.33 (m, 5H), 2.06-1.80 (m, 4H).

MS (FAB) 359 (M + 1) / phy

Scheme 20

@ 1 NHBOC Et 3 N, PtO _{2 -} NHBOC _{H 2 (EtOH} Pd (PPh ₃ ) Cl ₂ 1 at Cul, NEt ₃ 20-2

1) NaOH

2) EDC, HOBT ' NMM.

MeNHOMe * HCl

O

20-9. R = BOC

20-10. R = H

-Tsa, _CH2 Cl2

Scheme 20 (2nd part)

4-methoxybenzylamine, DPPF, PdCDBAh, NaOtBu, toluene

2M3 [3- (6-Bromo-pyridin-2-yl) -propyl] - (2-oxo-ethyl) -carbamic acid tert-butyl ester 2)

A solution of 111 g (468 mmol) of 2,6-dibromo-pyridine (20-1) and 80.0 g (515 mmol) of N-BOC-propargyl-amine in 500 ml of triethylamine is treated with 2.23 at 0 ° C. g (11.7 mmol) of copper (I) iodide. Argon was bubbled through the reaction mixture, and then 8.22 g (11.7 mmol) of dichlorobis (triphenylphosphine) palladium (II) was added. The solution was stirred at 0 ° C for 1 hour and then at room temperature for 16 hours. The solution is diluted with 250 ml of ether and washed four times with 100 ml of water. The organic extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give the product (20-2).

1 H NMR (CDCl 3, 300 MHz): δ 7.53-7.34 (m, 3H), 4.82-4.80 (br s, 1H), 4.18-4.17 (d, 2 H, 1.46 (s, 9H).

3- (2 - {[3- (6-bromo-pyridin-2-yl) -propyl] -tert-butoxycarbonyl-amino} -ethyl-amino) (20-3)

To a solution of 79.8 g (257 mmol) of the product (20-2) in 350 mL of ethanol and 26.8 mL (193 mmol) of triethylamine was added 2.91 g (12.8 mmol) of platinum oxide. After stirring under a hydrogen atmosphere for 4 hours, the solution was filtered through celite and concentrated in vacuo. The crude product was dissolved in 200 mL of ethyl acetate and washed four times with 250 mL of water and once with 250 mL of saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 10% ethyl acetate in chloroform to give the product (20-3).

»·· 4

4 • 4 ·· 4

4 4

4 4 4 4 4

4 4 4 4

44 * 44

1 H NMR (CDCl 3, 400 MHz): δ 7.48-7.42 (t, 1H), 7.32-7.29 (d, 1H), 7.13-7.10 (d, 1H), 4.71-4.70 (br s, 1H), 3.18-3.09 (m, 2H), 2.82-2.77 (t, 2H), 1.96-1.85 (m, 2H), 1.44 (s, 9H).

3- (6-Bromo-pyridin-2-yl) -propylamine hydrochloride (20-4)

A solution of 3.33 g (10.5 mmol) of the product (20-3) in 150 ml of ethyl acetate was saturated with hydrogen chloride gas and stirred at room temperature for 2 hours. The solvent was removed in vacuo to give the product (20-4). The crude product was used in the following synthesis without further purification.

[3- (6-Bromo-pyridin-2-yl) -propylamino] -acetic acid ethyl ester (20-5)

A solution of 3- (6-bromo-pyridin-2-yl) -propylamine (20-4) (25.6 g, 89.1 mmol),

46.5 ml (267 mmol) of diisopropyl-ethylamine, 28 ml (490 mmol) of acetic acid and 10.9 g (107 mmol) of ethyl glyoxylate in 200 ml of methanol are stirred at room temperature for 1 hour. 98.0 ml (98.0 mmol) of a 1M solution of sodium cyanoborohydride in tetrahydrofuran is slowly pumped into the mixture by syringe over 4 hours. The solution was stirred for 12 hours, the solvent was removed in vacuo, the residue was treated with chloroform and filtered. The solution was washed with 10% sodium carbonate solution, dried over sodium sulfate and the solvent removed in vacuo to give the crude amine. The crude product was purified by silica gel column chromatography eluting with 7% methanol in chloroform. The product (20-5) is obtained in a 3: 2 mixture of ethyl and methyl esters.

1 H NMR (CDCl 3, 300 MHz): δ 7.47-7.42 (t, 1H), 7.31-7.27 (t, 1H),

7.13-7.10 (d, 1H), 4.20-4.14 (m, 2H), 3.39 (s, 2H), 2.85-2.75 (m, 2H),

2.68-2.63 (t, 2H), 1.96-1.88 (m, 2H), 1.29-1.24 (m, 3H).

Μ «Ι« «*« 9

9 »9 9

99

999 »99

99 »» 9 9 • 9 9 ♦

9 9 9

9 9 9

9 99 {[3- (6-Bromo-pyridin-2-yl) -propyl] -terc. butoxy-carbonyl-amino-iacetate (20-6)

To a solution of 17.6 g (58.6 mmol) of ethyl [3- (6-bromo-pyridin-2-yl) -propylamino] -acetic acid (20-5) in 200 ml of tetrahydrofuran is added 15.3 g (70, 3 mmol) di-tert. butyl dicarbonate. After stirring at room temperature for 16 hours, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with 5% methanol in chloroform to give the product (20-6).

1 H NMR (CDCl 3, 300 MHz): δ 7.47-7.42 (m, 1H), 7.32-7.28 (t, 1H), 7.16-7.10 (t, 1H), 4 22-4.15 (q, 2H), 3.95-3.85 (d, 2H), 3.38-3.29 (m, 2H), 2.80-2.75 (t, 2H) ), 2.03-1.91 (m, 2H), 1.46-1.44 (m, 9H), 1.31-1.23 (m, 3H).

[3- (6-Bromo-pyridin-2-yl) -propyl] - [(methoxy-methyl-carbamoyl) -methyl] -carbamic acid tert-butyl ester (20-7)

To a solution of 23.4 g (58.4 mmol) of the product (20-6) in 200 mL of ethanol was added 100 mL (100 mmol) of a 1M solution of sodium hydroxide in water. After stirring at 50 ° C for 1 hour, 10.3 ml (4.75 mmol) of a 12M solution of hydrochloric acid in 50 ml of ethanol are added and the reaction mixture is evaporated to give an oily residue which is evaporated three times from ethanol and then three times from acetonitrile to give a yellow solid. The product is dried under vacuum at less than 0.267 kPa for 2 hours. The residue was suspended in 180 ml of acetonitrile and 180 ml of chloroform and 41.7 ml (379 mmol) of NMM, 11.9 g (122 mmol) of N, O-dimethyl-hydroxylamine hydrochloride, 10.2 g ( 75.9 mmol) of HOBT and 14.5 g (75.9 mmol) of EDC. After stirring for 15 hours, the mixture was evaporated to dryness and the residue suspended in ethyl acetate, which was then washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over sodium sulfate.

Evaporation of the solvent followed by evaporation from toluene to remove NMM gave the product (20-7) as a yellow oil.

TLC Rf = 0.49 (silica, chloroform / ethyl acetate / methanol 70: 25: 5) @ ¹ H NMR (CDCl3, 300 MHz): .delta.7.48-7.41 (m, 1H), 7 32-7.28 (t, 1H), 7.17-7.11 (t, 1H), 4.14 (s, 2H), 3.73-3.70 (d, 3H), 3.39- 3.30 (m, 2H).

3.18 (s, 3H), 2.80-2.75 (t, 2H), 2.02-1.91 (m, 2H), 1.45 (m, 9H).

target. (3- (6-Bromo-pyridin-2-yl) -propyl] - (2-oxo-ethyl) -carbamic acid butyl ester (20-8)

To a stirred solution of 14.9 g (35.7 mmol) of the product (20-7) in 100 mL tetrahydrofuran at -78 ° C was added dropwise 53.6 mL (53.6 mmol) 1.0 M solution of DIBAL in hexanes. After 1 hour the mixture was allowed to warm to room temperature and quenched by careful addition of 20 mL of methanol. After addition of 200 ml of 1.0 M Rochelle salt solution, the cooling bath was removed. The mixture was stirred for 1.0 hour and then diluted with diethyl ether. After stirring for another 30 minutes, the organic portion was separated and dried over magnesium sulfate. Evaporation of the solvent gave the crude aldehyde (20-8) as a colorless oil.

'H NMR (CDCl3, 300 MHz): δ 9.59-9.56 (d, 1H), 7.48-7.43 (t, 1H),

7.32-7.26 (m, 1H), 7.14-7.07 (m, 1H), 3.53-3.26 (m, 4H), 2.80-2.72 (m, 2H) 1.00-1.93 (m, 2H), 1.44 (s, 9H).

3- (5-Ethoxy-pyridin-3-yl) -propionic acid tert-butyl ester (20-9)

A mixture of 0.671 g (1.88 mmol) of the crude aldehyde (20-8), 0.651 g (2.44 mmol) of the amine (15-8), 0.107 mL (1.88 mmol) of acetic acid, 1.54 g (18, 8 mmol) of sodium acetate and 1.20 molecular sieves in powder form in 15 ml of 2-propanol are stirred for 20 minutes. The reaction mixture was quenched

Cool to 0 ° C, then add 0.354 g (5.64 mmol) of sodium cyanoborohydride. After stirring for 6 hours, the pH of the mixture was brought to pH ~ 2 by addition of 1N hydrochloric acid solution. The solution was stirred for an additional 10 minutes and then 20 mL of ethyl acetate was added. The pH is brought to about 11 by addition of a 10% potassium carbonate solution. The organic portion was extracted with ethyl acetate, dried over sodium sulfate and removed in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 70: 25: 5 chloroform: ethyl acetate: methanol to give the product (20-9) as a yellow oil in 95% yield.

¹ H NMR (CDCl ₃₎ 300 MHz): δ 8.19-8.18 (d, 1H), 8.14-8.13 (d, 1H), 7.48-7.42 (t, 1H) 7.32-7.26 (m, 1H); 7.23-7.20 (m, 1H); 7.11-7.08 (m, 1H); 4.16-4.02 (m, 1H); 3H), 3.30-3.18 (m, 4H), 2.74-2.45 (m, 7H), 1.921.86 (t, 2H), 1.45-1.38 (m, 21H) .

target. 3- {2- [3- (6-Bromo-pyridin-2-yl) -propylamino-ethylamino} -3 (S) - (5-ethoxy-pyridin-3-yl) -propionic acid butyl ester (20-10)

To a solution of 3- (5-ethoxy-pyridin-3-yl) -propionic acid tert-butyl ester (20-9) (0.085 g, 0.141 mmol) in dichloromethane (5 mL) was added p-toluenesulfonic acid (0.161 g, 0.847 mmol). . The reaction mixture was stirred at room temperature for 2 hours and then neutralized by addition of 1N sodium hydroxide solution. The organic portion was extracted three times with 25 mL of chloroform, dried and concentrated in vacuo. This gave 0.069 g of crude product (20-10) which was not purified (yield 96%).

¹ H NMR (CDCl 3, 300 MHz): δ 8.23-8.21 (m, 2H), 7.45 (s, 1H), 7.407.35 (m, 1H), 7.28-7.25 ( t, 1H), 7.04-7.01 (d, 1H), 6.28 (br s, 2H), 4,394.33 (t, 1H), 4.00-3.92 (q, 2H), 3 40-3.35 (m, 2H); 3.28-3.22 (m, 1H);

3.15-2.90 (m, 4H), 2.79-2.71 (m, 3H), 2.14-2.01 (m, 2H), 1.34-1.26 (m,

12H).

• • •

target. 3- {3- [3- (6-Bromo-pyridin-2-yl) -propyl] -2-oxo-imidazolidin-1-yl} -3 (S) - (5-ethoxy-pyridin-3-yl) -butyl ester Propionic acids (20-11)

To 0.80 g (1.57 mmol) of a stirred solution of the product (20-10) and 0.823 mL (4.72 mmol) of diisopropylethylamine in 10 mL of dichloromethane at 0 ° C was added 0.333 g (1.65 mmol). p-nitrophenyl-chloro-formate. After stirring for 30 minutes, 10 ml of dioxane was added to the solution, and the mixture was then refluxed for 4 hours. Ethyl acetate (100 ml) was added and the organics were washed with 10% potassium carbonate solution, dried and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with a 70:20:10 mixture of chloroform, ethyl acetate and methanol to give the product (20-11).

1 H NMR (CDCl 3, 400 MHz): δ 8.22-8.18 (dd, 1H), 8.14-8.13 (t, 1H), 7.46-7.37 (m, 1H), 7.31 -7.24 (m, 1H), 7.20-7.16 (m, 1H), 7.11-7.09 (d, 1H), 4.09-4.04 (q, 2H), 3 , 34-3.16 (m, 2H), 2.99-2.87 (m, 2H), 2.772.69 (m, 2H), 2.63-2.46 (m, 2H), 1.97 -1.88 (m, 2H); 1.44-1.37 (m, 12H).

MS M + 1 = 533.3.

3 (S) - (5-Ethoxy-pyridin-3-yl) -3- (3- {3- [6- (4-methoxy-benzylamino) -pyridin-2-yl] -propyl} - tert-butyl ester - 2-Oxo-imidazolidin-1-yl) -propionic (20-12)

To a stirred solution of 0.075 g (0.142 mmol) of the product (20-11) in 3 mL of toluene was added 0.0041 g (0.0071 mmol) of Pd (DBA) 2, 0.0039 g (0.0071 mmol) of DPPF and 0. 0.163 g (0.170 mmol) of NaOt-Bu, followed by 0.0204 mL (0.156 mmol) of p-methoxybenzylamine. The resulting solution was heated at 110 ° C for 2 hours. The solution was cooled and the solvent was removed in vacuo. The product is purified on silica gel

462.

chromatography eluting with 10% ethanol in ethyl acetate to give the product (20-12).

1 H NMR (CDCl 3, 400 MHz): δ 821-8.20 (d, 1H), 8.14-8.13 (d, 1H),

7.33-7.25 (m, 3H), 7.19-7.17 (t, 1H), 6.87-6.84 (d, 2H), 6.45-6.43 (d, 1H), 6.21-6.18 (d, 1H), 5.48-5.42 (t, 1H), 5.26 (br s, 1H), 4.38-4.37 (d, 2H), 4 3.90-4.01 (q, 2H), 3.79 (s, 3H), 3.31-3.18 (m, 5H), 3.07-2.87 (m, 3H), 2.63 -2.58 (t, 2H), 1.95-1.84 (m, 2H), 1.49-1.39 (m, 12H).

3 (S) - (5-Ethoxy-pyridin-3-yl) -3- (3- {3- [6- (4-methoxy-benzylamino) -pyridin-2-yl] -propyl} -2- oxo-imidazolidin-1-yl) -propionic acid (20-13)

To a stirred solution of 0.028 g (0.047 mmol) of the product (20-12) in 10 mL of dichloromethane was added 1 mL of trifluoroacetic acid. After 1 hour the solvent was removed in vacuo and purified by azeotropic distillation with 15 ml toluene. The resulting residue was purified by silica gel column chromatography eluting with a 25: 10: 1: 1 mixture of ethyl acetate, ethanol, water and ammonium hydroxide, followed by 15: 10: 1: 1 to give the product (20-13) as a white solid. substances.

¹ H NMR (CDCl 3, 400 MHz): δ 8.21-8.20 (d, 2H), 7.50-7.46 (t, 1H), 7.31-7.26 (m, 2H), 7.19 (s, 1H), 6.88-6.85 (d, 2H), 6.42-6.40 (d, 1H),

6.34- 6.32 (d, 1H), 5.69-5.63 (m, 1H), 5.30 (s, 1H), 4.43-4.41 (d, 2H), 4.09- 4.01 (q, 2H), 3.77 (s, 3H), 3.75-3.44 (m, 3H), 3.24-2.86 (m, 4H), 2.79-2, 67 (m, 3H), 2.03-1.90 (m, 2H), 1.44-1.41 (t, 3H).

MS (FAB) 534 (M + 1).

3- {3- [3- (6-Amino-pyridin-2-yl) -propyl] -2-oxo-imidazolidin-1-yl} -3 (S) - (5-ethoxy-pyridin-3-yl) -propionic acids (20 -14)

To a stirred solution of 0.031 g (0.052 mmol) of the product (20-13) in ml of dichloromethane was added 1 ml of trifluoroacetic acid. The solution was stirred at 85 ° C for 16 hours. The solvent was removed in vacuo and the mixture was azeotroped twice with 15 ml of toluene. The resulting residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate, ethanol, water and ammonium hydroxide in a ratio of 15: 10: 1: 1, followed by 10: 10: 1: 1 to give the product (20-14) as a white solid. ¹ H NMR (CD 3 OD, 400 MHz): δ 8.13-8.10 (m, 2H), 7.59-7.54 (t, 1H), 7.387.35 (m, 1H), 6, 60-6.57 (d, 2H), 5.53-5.47 (q, 1H), 4.15-4.09 (q, 2H), 3.64-3.57 (m, 1H), 3.47-3.41 (m, 1H), 3.28-3.21 (m, 2H), 3.072.90 (m, 3H), 2.76-2.61 (m, 3H), 2, O 2-1.83 (m, 2H), 1.42-1.38 (t, 3H). MS (FAB) 414 (M + 1).

Scheme 21

3-Bromo-6-chloro-5-nitropyridine (21-2)

A suspension of 3.33 g (24.8 mmol) of copper (I) chloride in 200 ml of anhydrous methyl cyanide is treated at 65 ° with 3.13 ml (26.3 mmol) of tert-butyl nitrite, followed by dropwise addition of a solution of the product ( 211) in 60 ml methyl cyanide. The resulting mixture was stirred at 65 ° C under argon for 2 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and 3% hydrochloric acid (60 ml). The organic portion was washed thoroughly with 3% hydrochloric acid, water and 60 ml of saturated sodium chloride solution, dried, and then filtered. Concentration gave the product as a brown solid, which was purified by silica chromatography. 4 4

4 444 ^W 44 44 444 444 eluting with 25% ethyl acetate in hexane to give the product (21-2) as a yellow crystalline solid.

TLC Rf = 0.60 (25% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl 3): δ 8.70 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H).

(3-Nitro-5-bromo-pyridin-2-yloxy) -acetic acid methyl ester (21-3)

To a suspension of 131 mg (55 mmol) of a 60% solution of sodium hydride in 20 mL of tetrahydrofuran at 0 ° was added 450 mg (5.05 mmol) of methyl glycolate. The resulting solution was stirred under argon for 0.5 h, then treated with the product solution (21-2). After stirring at 0 ° for 0.5 h, the reaction was diluted with ethyl acetate and washed thoroughly with 80 mL of saturated sodium bicarbonate solution, 80 mL of water and 80 mL of saturated sodium chloride solution. After drying, filtration and concentration, the resulting product (21-3) is obtained as a yellow solid.

TLC Rf = 0.70 (25% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl 3): δ 8.46 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H) 5.15 (s, 2H) 3.78 (s, 3H).

2-oxo-2,3-dihydro-1H-4-oxo-1,5-diaza-7-bromo-naphthalene (21-4)

A mixture of 1.5 g (5.12 mmol) of product (21-3) and 1.37 g (11.5 mmol) of tin powder was treated with 10 mL of concentrated hydrochloric acid. The reaction mixture was heated at 80 ° C for 2 hours and then cooled and concentrated. The residue was partitioned between chloroform and saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, and then dried, filtered and concentrated to give the product as a yellow solid which was purified by chromatography eluting

767 ·· 0 0 · 0 0 0 0 0 0 0

50% hexane / ethyl acetate solution. The product (21-4) was obtained as a yellow solid.

TLC Rf = 0.65 (50% ethyl acetate in hexane).

¹ H NMR (300 MHz, DMSO-d 6): δ 10.81 (br, s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 2, 4 Hz, 1H), 4.81 (s, 2H).

3- (2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl) -acrylic acid tert-butyl ester (21-5)

A mixture of 1.12 g (4.89 mmol) of the product (21-4), 298 mg (1.0 mmol) of tri-o-tolylphosphine, 110 mg (0.49 mmol) of palladium acetate is placed in a 100 ml flask. and 0.86 ml (5.87 mmol) of triethylamine in 20 ml of dimethylformamide. The reaction mixture was degassed in the presence of argon, and then t-butyl acrylate (752 mg, 5.87 mmol) was added. The reaction vessels were sealed and heated to 100 ° C for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered and washed with sodium bicarbonate, water and saturated sodium chloride solution. The product was dried, filtered and concentrated to give the product which was purified by silica gel column chromatography eluting with 25% hexane in ethyl acetate. The product (21-5) is obtained as a yellow solid.

TLC Rf = 0.60 (25% ethyl acetate in hexane).

¹ H NMR (300 MHz, DMSO-d 6): δ 10.91 (br, s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 16 Hz) 1 H), 7.42 (d, J = 2.4 Hz, 1H), 6.35 (d, J = 16 Hz, 1H), 4.84 (s, 2H), 1.48 (s , 9H).

3 (S) - [Benzyl- (1 (R) -phenylethyl) -amino] -3- (2-oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-) tert-butyl ester 7-yl) propionic acid (21-6)

A solution of 0.82 g (3.87 mmol) of N-benzyl-α- (R) -methylbenzylamine in 25 ml of tetrahydrofuran at 0 ° C is treated with 1.6 ml of a 2.5 M solution of n.

161

4 · · · 4 · · · · · · · · · · ·

4 · · · ·

9 9 ··

4 · 9 ·

9

4,444 44 butyl lithium in hexanes. The resulting solution was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. Add 0.485 g (1.76 mmol) of a solution of acrylate (21-5) in 5 mL of tetrahydrofuran. After stirring at -78 ° C for 15 minutes, 5 mL of saturated aqueous ammonium chloride solution was added and the cooling bath was removed. The reaction mixture was allowed to warm 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 40% ethyl acetate in hexanes to give the β-aminoester (21-6) as a yellow oil.

TLC Rf = 0.3 (40% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl 3): δ 1H NMR 8.70 (br, s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.4-7.2 (10H) 7.12 (d, J = 1.8 Hz, 1H), 4.80 (s, 2H), 4.42 (m, 1H), 3.91 (q, J = 6.7 Hz, 1) H), 3.69 (d, J = 7.2 Hz, 1H), 3.62 (d, J = 7.2 Hz, 1H), 2.46 (m, 2H), 1.34 (d) J = 7.0 Hz, 3H), 1.29 (s, 9H).

3 (S) -Amino-3- (2-oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl) -propionic acid tert-butyl ester (21-7)

A mixture of 0.22 g (0.44 mmol) of dibenzylamine (21-6) in a mixture of 26 ml of ethanol, 3 ml of water and 1.0 ml of acetic acid is degassed in the presence of argon and treated with 100 mg of palladium hydroxide. The reaction mixture was placed under 1 atm of hydrogen. After stirring for 18 hours, the reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography eluting with 20% ethanol, ammonium hydroxide and water 20: 1: 1 to 80% ethyl acetate to give tert-butyl ester (21-7) as a white solid.

TLC Rf = 0.5 (20: 1: 1: 1-80% ethyl acetate 20% ethanol / ammonium hydroxide / water).

TM

9 9 9999 9 9 9 9 9 9 9 9 9 9 9 9 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

¹ H NMR (300 MHz, CD 3 OD): δ 7.89 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H), 4.81 (s, 2H ), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H).

target. 3 (R) - [Benzyl- (1-phenylethyl) -amino] -3 (S) - (2-thioxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7) butyl ester -yl) -propionic acids (21-8)

A solution of 0.22 g (0.44 mmol) of the product (21-6) in 0.098 g (0.243 mmol) of anhydrous tetrahydrofuran was treated with Lawesson's reagent and the reaction mixture was stirred at room temperature for 1.5 hours. 500 mg of silica gel was added to the mixture, the solvent was removed under reduced pressure and the product was eluted from silica using 25% ethyl acetate in hexane to give the product (21-8) as a yellow solid. TLC Rf = 0.7 (40% ethyl acetate in hexane).

¹ H NMR (300 MHz, CD 3 OD): δ 9.82 (br, s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.47.2 (11H), 5.08 (s, 2H), 4.42 (m, 1H), 3.91 (q, J = 6.7 Hz, 1H), 3.69 (d, J = 7.2 Hz, 1H), 3 62 (d, J = 7.2 Hz, 1H), 2.46 (m, 2H), 1.34 (d, J = 7.0 Hz, 3H), 1.29 (s, 9H).

target. 3 (S) -Amino-3- (2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl) -propionic acid butyl ester (21-9)

A solution of 1.0 g (1.9 mmol) of the product (21-8) in 10 mL of anhydrous diethyl ether was treated dropwise at 0 ° with 2.09 mL of a 1.0 M solution of lithium aluminum hydride in diethyl ether. The solution was stirred at 0 ° C for 30 minutes and then quenched by the sequential addition of 0.3 mL of water and 0.08 mL of 15% sodium hydroxide solution. After adding 1 g of celite, the reaction mixture was filtered through a pad of celite. The filtrate was evaporated and the residue was purified by flash chromatography eluting with 65% ethyl acetate in hexanes to give the dibenzylamine intermediate as a yellow oil.

TLC Rf = 0.4 (65% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl 3): δ 1H NMR 7.61 (d, J = 1.8 Hz, 1H), 7.4-7.2 (10H), 6.87 (d, J = 1, 8 Hz, 1H), 4.41 (m, 2H), 4.36 (m, 1H), 3.91 (q,

J = 6.7 Hz, 1H), 3.8 (brs, 1H), 3.69 (m, 2H), 3.42 (m, 2H), 2.46 (m, 2H),

1.34 (d, J = 7.0Hz, 3H), 1.29 (s, 9H).

The material was deprotected using palladium hydroxide in ethanol to give the product (21-9) as a white solid.

TLC Rf = 0.5 (20: 1: 1: 1-80% ethyl acetate 20% ethanol / ammonium hydroxide / water).

¹ H NMR (300 MHz, CD 3 OD): δ 7.59 (d, J = 1.7 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 4.41 (m, 2H) 4.30 (m, 1H), 3.41 (m, 2H), 2.6, (m, 2H), 1.41 (s, 9H).

3 (S) - (2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl) -3- {2-oxo-3- [3- (5) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid (21-10)

The resulting product (21-10) was prepared using intermediates (2-9A) and (21-7) according to the procedure described in Scheme 2.

High resolution mass spectrum: Calculated = 418.2198; found = 481.2193.

3 (S) - (2,3-Dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) propyl] -imidazolidin-1-yl} propionic acid (21-11)

The resulting product (21-11) was prepared using intermediates (2-9A) and (21-8) according to the procedure described in Scheme 2.

High resolution mass spectrum: Calculated = 467.2417; found = 467.2401.

Scheme 22 ///

«« 3 • • • • 44 4 • • 4 • · • • • * • • 4 »4 4 4 φ 4 • • 4 4 4 • • • 4 4 4 • 4 4 4 • 4 • 4 • 4 4 4 4 4 4 · 4 ·

3-oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-7-bromo-naphthalene (22-2)

A solution of 4.8 g (32 mmol) of the product (22-1) in 160 mL of methanol was treated dropwise at -15 ° with 25.7 g (161 mmol) of bromine. Mo 0,5

• • r · • • • 999 • « ♦ • · • • • 9 9 99 • 9 9 9 99 • 9 9 9 9 • • • 4 • 9 9 9 9 9 99 • 9 • 9 9 • 99 9 9 99

After stirring at -15 ° C for 1 h, the reaction mixture was allowed to warm to room temperature and stirred overnight. The formed white precipitate was filtered and washed with cold methanol to give the product (22-2) as a white solid.

TLC Rf = 0.65 (50% ethyl acetate in hexane).

¹ H NMR (300 MHz, DMSO-d 6): δ 11.2 (br s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.4) Hz, 1H), 4.76 (s, 2H).

3 (S) -Amino-3- (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl) -propionic acid tert-butyl ester (22-3)

The bromide (22-2) is converted to the aminoester (22-3) according to Scheme 21. TLC Rf = 0.5 (12% ethanol: ammonium hydroxide / water 20: 1: 1-88% ethyl acetate).

¹ H NMR (300 MHz, CD 3 OD): δ 8.04 (d, J = 1.7 Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H), 4.76 (s, 2H) ), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H).

3 (S) -Amino-3- (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalene-7-propionic acid tert-butyl ester (22-4)

The bromide (22-2) is converted to the aminoester (22-4) according to the procedure of Scheme 21.

TLC Rf = 0.5 (20% 1: 1: 1-80% ethyl acetate 20% ethanol: ammonium hydroxide / water) ¹ H NMR (300 MHz, CD 3 OD): δ 8.04 (d, J = 1.7) Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H), 4.76 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1 41 (s, 9H).

3 (S) - (3-Oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl) -3- {2-oxo-3- [3- (5, 5-oxo-3,4-dihydro-2H-1-oxa-4,5) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid (22-5)

99 • 999 9 * 9 99 9 9 99 9 99 9 9 9 9 99 • 9 » 9 9 • 1 » 9 9 • • 9 9 9 9 9 9 9 9 »9 99 999 99 9 99 99

The resulting product (22-5) was prepared using intermediates (2-9A) and (22-3) according to the procedure described in Scheme 2.

High resolution mass spectrum:

calcd. = 481.2198; found = 481.2194.

3 (S) - (3,4-Dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl) propyl] -imidazolidin-1-yl} -propionic acid (22-6)

The resulting product (22-6) was prepared using intermediates (2-9A) and (22-4) according to the procedure described in Scheme 2.

High resolution mass spectrum: Calculated = 467.2417; found = 467.2411.

Scheme 23 • / Week

23-4

H ₂ , Pd / C

O

22 £ furo- [2,3-b] pyridine-5-carboxaldehyde (23-2)

The alcohol solution (23-1) (M. Bhupathy et al., J. Heterocycl. Chem., 1995, 32, 1283-1287) is treated with an excess (10 eq) of oxide. The reaction mixture was stirred at room temperature for 16 hours and then filtered through celite. Evaporation gave the product (23-2) as a white solid.

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

1 H NMR (300 MHz, CDCl 3): δ 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-Amino-3- (furo [2,3-b] pyridin-5-yl) -propionic acid ethyl ester (23-3)

A solution containing 1.5 g (10 mmol) of aldehyde (23-2), 1.6 g (20 mmol) of ethyl hydrogen malonate and 3.8 g (50 mmol) of ammonium acetate in 125 ml of anhydrous ethanol was heated for 8 hours. to reflux temperature. After cooling to room temperature, the solvent was evaporated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic portion was removed, dried and concentrated. Chromatography of the residue gives the amino-ester (23-3) as a waxy solid.

TLC Rf = 0.5 (20% ethanol solution, ammonium hydroxide and water in a ratio of 20: 1: 1-80% ethyl acetate) ¹ H NMR (300 MHz, CD3OD): δ 8.34 (d, J = 1, 7 Hz, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 6.78 (d, J = 1.7 Hz) 1 H, 4.62 (m, 1 H), 4.13 (q, J = 7.5 Hz, 2 H), 3.20 (br, s, 2 H), 2.76 (m, 2 H), 1 23 (t, J = 7.5Hz, 3H).

3-furo [2,3-b] pyridin-6-yl-3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2- yl) propyl] imidazolidin-1-yl] propionic acid (23-4)

The resulting product (23-4) was prepared using intermediates (2-9A) and (23-3) according to the procedure described in Scheme 2.

• · · ·

TLC Rf = 0.30 (50% ethanol: ammonium hydroxide / water 20: 1: 1 ~ 50% ethyl acetate).

FAB MS found 450.1 (M + H).

3- (2,3-dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) ) propyljimidazolidin-yl} propionic acid (23-5)

A solution of 360 mg (0.80 mmol) of the product (23-4) in 10 mL of methanol was treated with 100 mg of a 10% palladium on charcoal solution and stirred for 18 hours under a hydrogen atmosphere. The catalyst was removed by filtration through celite and the residue purified by chromatography eluting with 75% ethanol, ammonium hydroxide and water 20: 1: 1 and 25% ethyl acetate to give (23-5) as a colorless glass. TLC Rf = 0.30 (50% ethanol, ammonium hydroxide and water 20: 1: 1 -50% ethyl acetate)

FAB MS found 452.2 (M + H).

Scheme 24

MnO ₂ ch ₂ or ₂

HO ₂ CT CO ₂ Et NH ₄ Ac, EtOH

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

The alcohol solution (24-1) (JM Hoffman, Jr., US 4,808,595) was treated with an excess of manganese dioxide (10 eq) and the reaction mixture was stirred at room temperature for 16 hours, then filtered through celite and filtered. evaporate to give the product (24-2) as a white solid.

¹ H NMR (300 MHz, CDCl 3): δ 10.18 (s, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8 17 (d, J = 1.7 Hz, 1H); 7.89 (d, J = 1.8 Hz, 1H); 7.10 (d, J = 1.7 Hz, 1H).

3-Amino-3- (furo- [3,2-b] pyridin-5-yl) -propionic acid ethyl ester (24-3)

A solution containing 1.5 g (10 mmol) of aldehyde (24-2), 1.6 g (20 mmol) of ethyl hydrogen malonate, and 3.8 g (50 mmol) of ammonium acetate in 125 ml of anhydrous ethanol with 8 The mixture was heated at reflux for 1 hour. After cooling to room temperature, the solvent was evaporated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic portion was removed, dried and concentrated. Chromatography of the residue gives the aminoester (24-3) as a waxy solid.

TLC Rf = 0.5 (20: 1: 1-80% ethyl acetate in 20% ethanol, ammonium hydroxide and water) ¹ H NMR (300 MHz, CD 3 OD): δ 8.58 (d, J = 1, 7 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 6.98 (d, J = 1.7 Hz) 1H, 4.62 (t, J = 7.2Hz, 1H), 4.09 (q, J = 7.5Hz, 2H), 2.76 (m, 2H), 2.20 (br , s, 2H), 1.21 (t, J = 7.5Hz, 3H).

3- (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine] - 2-yl) propyl] -imidazolidin-1-yl} propionic acid (24-4)

The resulting product was prepared using intermediates (2-9A) and (24-3) according to the procedure described in Scheme 2.

TLC Rf = 0.56 (75% ethanol, ammonium hydroxide and water 20: 1: 1 - 25% ethyl acetate)

High resolution mass spectrum:

calcd. = 450, 2117; found = 450, 2136.

• 4 KW · KW

3- (2,3-dihydrofuran [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- 1,8] naphthyridin-2-yl) propyl] imidazolidin-1-yl} -propionic acid (24-5)

A solution of 181 mg (0.38 mmol) of the product (24-4) in 5 mL of acetic acid was treated with 100 mg platinum oxide and the reaction mixture was stirred under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration through celite and the residue was purified by chromatography eluting with 75% ethanol: ammonium hydroxide and water (20: 1: 1) to 25% ethyl acetate to give the product (24-5) as a colorless glass.

TLC Rf = 0.50 (20: 1: 1 - 25% ethyl acetate solution, 75% ethanol, ammonium hydroxide and water)

High resolution mass spectrum: calculated = 452 2298; found = 452 2238.

9 999

BocHN '

Scheme 25 every ₂ h

NH, CO ₂ Me

25x1 'NH ₂ 25-2 (X = CH) 25-2 (X = N)

EDC, HOAT, NMM, DMF

eocHN -'- “ ² “ ⁶ 25x2a (X = CH) 25x2k (X = N)

1. HOAc, 65 [deg.]

2. HCl, EtOAc

N.

_n A _n A / CO ₂ H ₂

25x5a (X = CH)

25x5b X = N

25-4a (X = CH) 25-4b (X = N) N- (S) - (2-amino-phenyl) -3-tert-butoxycarbonylamino-succinamic acid methyl ester (25-3a)

A mixture of 5.0 g (20.2 mmol) Boc-L-aspartic acid β-methyl ester (25-1), 22 g (20.2 mmol) o-phenylene diamine (25-2a), 3.9 g (20 mmol) EDC, 0.28 g (2.02 mmol) HOAT and 6.7 ml (60.7 mmol) NMM in 50 ml dimethylformamide were stirred at room temperature for 18 hours. The solution is diluted with 250 ml of ethyl acetate and washed with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated sodium chloride solution, and then dried and evaporated. The resulting product (25-3a) was obtained as a yellow solid.

Μ

TLC R f = 0.50 (95% chloroform in 5% isopropanol) ¹ H NMR (300 MHz, CDCl 3): δ 8.10 (br, s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.8Hz, 1H) 6.78 (m, 1H), 5.8 (br d, 1H), 4.65 (m, 1H), 3.76 (s, 3H), 3.15 (dd, J = 4.6, 16 Hz, 1H), 2.90 (dd, J = 5.1, 6 Hz, 1H), 1.48 (s, 9H) .

3 (S) -Amino-3- (benzimidazol-2-yl) -propionic acid methyl ester (25-4a)

1.0 g (3 mmol) of ester (25-3a) was dissolved in 50 ml of acetic acid and the solution was heated to 65 ° for 2 hours. The solvent was removed to give the Boc-protected intermediate product as a white solid. A solution of 920 mg (2.43 mmol) of the crude product was cooled to 0 ° and the solution was treated with hydrogen chloride gas to give the product (25-4a) as a tan solid.

¹ H NMR (300 MHz, CD 3 OD): δ 7.80 (m, 2H), 7.35 (m, 2H), 5.98 (m, 1H), 3.80 (m, 2H), 3.76 (s, 3 H).

3 (S) - (Benzimidazol-2-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl] imidazolidine- 1-yl) -propionic acid (25-5a)

The resulting compound (25-5a) was prepared using intermediates (29A) and (25-4a) according to the procedure described in Scheme 2.

TLC Rf = 0.30 (50% ethanol, ammonium hydroxide and water 20: 1: 1 - 50% ethyl acetate).

FAB MS found 449.2 (M + H).

3 (S) - (1H-Imidazo [4,5-c] pyridin-2-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) naphthyridin-2-yl) propyl] -imidazolidin-1-yl) propionic acid (25-5b)

The resulting product (25-4b) was prepared according to the procedure described above by substituting 3,4-diaminopyridine for o-phenylene diamine.

TLC Rf = 0.25 (50% ethanol, ammonium hydroxide and water 20: 1: 1 - 50% ethyl acetate).

FAB MS found 450.2 (M + H).

Scheme 26

NMM, DMF

HO Y

H

BocHN

CO ₂ Me

1. DEAD, Ph ₃ P THF

2. HCl, EtOAc

N,

♦ 4 4 • 4

4

4

4 // 3 N- (S) - (2-Hydroxy-phenyl) -3-tert-butoxy-carbonylamino-succinamic acid methyl ester (26-2)

A mixture of 5.0 g (20.2 mmol) Boc-L-aspartic acid β-methyl ester, 2.2 g (20.2 mmol) 2-amino-phenol (26-1), 3.9 g (20.2 mmol) mmol) EDC, 0.28 g (2.02 mmol) HOAT and 6.7 mL (60.7 mmol) NMM in 50 mL dimethylformamide were stirred at room temperature for 18 h. The solution is diluted with 250 ml of ethyl acetate and washed with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated sodium chloride solution, and then dried and evaporated. The resulting residue was purified by silica column chromatography eluting with ethyl acetate to give the product (26-2) as a white solid.

TLC R f = 0.55 (ethyl acetate) ¹ H NMR (300 MHz, CDCl 3): δ 7.23 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H ), 6.78 (m, 1H), 5.68 (brd, 1H), 4.65 (m, 1H), 3.76 (s, 3H), 3.15 (dd, J = 4.6) 16 Hz, 1H), 2.90 (dd, J = 5.1, 16 Hz, 1H), 1.48 (s, 9H).

3 (S) -Amino- (3-benzoxazol-2-yl) -propionic acid methyl ester (26-3)

2.0 g (6.0 mmol) of ester (26-2) was dissolved in 150 ml of anhydrous tetrahydrofuran using 1.58 g (6.0 mmol) of triphenylphosphine. The resulting solution was cooled to 0 °, and 1.53 g (6.2 mmol) of a solution in diethyl azodicarboxylate in 25 mL of tetrahydrofuran was added dropwise. Remove the cooling bath and stir the solution overnight at room temperature. The solution was concentrated and the residue purified by chromatography eluting with 75% ethyl acetate in hexane to give the Boc-linked ester as a colorless glass. A solution of the crude product (1.8 g, 5.0 mmol) in ethyl acetate was cooled to 0 ° C. ···· The cooled solution is treated with hydrogen chloride gas to give (263) as a tan solid.

¹ H NMR (300 MHz, CD 3 OD): δ 7.81 (m, 2H), 7.40 (m, 2H), 5.05 (t, J = 7.4 Hz, 1H), 3.72 (s 3H), 3.30 (m, 2H).

3 (S) - (Benzoxazol-2-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl] imidazolidin-1-yl) propionic acid (26-4)

The resulting product (26-4) was prepared using intermediates (2-9A) and (26-3) according to the procedure described in Scheme 2.

TLC Rf = 0.40 (50% ethanol, ammonium hydroxide and water 20: 1: 1 - 50% ethyl acetate).

FAB MS found 450.3 (M + H).

Scheme 27

27-4

methyl-4-bromo-pyrazole (27-2)

To a mixture of 4-bromopyrazole (10 g, 38 mmol) (27-1) and potassium carbonate (18.9 g, 136 mmol) in methyl cyanide (150 mL) was added methyl iodide (8.47 mL, 136 mmol) and the reaction mixture was stirred at RT for 16 h. at room temperature, then filtered and evaporated to give the product (27-2) as a yellow oil.

1 H NMR (300 MHz, CDCl 3): δ 7.44 (s, 1H), 7.38 (s, 1H), 3.90 (s, 3H).

3 (S) -Amino-3- (1-methyl-1H-pyrazol-4-yl) -propionic acid ethyl ester (27-3)

The resulting bromide (27-2) is converted to the aminoester (27-3) according to the procedure in Scheme 1.

1 H NMR (300 MHz, CD 3 OD): δ 7.81 (s, 1H), 7.58 (s, 1H), 4.80 (m, 1H), 4.05 (q, J = 7.0 Hz, 2 H), 3.89 (s, 3H), 3.00 (m, 2 H), 1.24 (t, J = 7.0 Hz, 3 H).

3 (S) - (1-Methyl-1H-pyrazol-4-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridine) 2-yl) propyl] -imidazolidin-1-yl) propionic acid (27-4)

The resulting product (27-4) was prepared using intermediates (2-9A) and (27-3) according to the procedure described in Scheme 2.

TLC Rf = 0.24 (ethyl acetate, ethanol, water, ammonium hydroxide = 15: 10: 1: 1). ¹ H NMR (300 MHz, CD 3 OD): δ 7.58 (s, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.38 (s, 1H), 6.62 (d J = 7.3 Hz, 1H), 5.38 (m, 1H), 3.83 (s, 3H), 3.143.53 (9H), 2.97 (m, 2H), 2.80 (t J = 6.1 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 1.93 (m, 4H).

9 * 9

9 9

9 10 «« · * ·

Scheme A

Synthesis of radioligand for SPA test

Scheme A (2nd part) ·· · * · «τη-

6NHCI

44 • • • • • • • • • • • • • • • • • • • • 44

Scheme A (3rd part) * 999 y / z

«99 99 ·· 9 ·· ·« 999

9 9 9 9 9 • 9 9 9

999 ·· ·· hcw ₂ n ^ X ^c ° ^2CH - ^{3H3 H} 'HNSO ₂ C ₃ H ₄ I

A-4

EDC, HOBT, NMM, DMF

• 8 «« · «

Scheme A (Part 4) 9

98 · »« 9 ·

9 9 9

9

9 9 • 9 99

A-10

N- (4-iodo-phenyl-sulfonyl-amino) -L-asparagine (A-2)

To a stirred solution of 4.39 g (33.2 mmol) of acid (A-1), 1.49 g (37.2 mmol) of sodium hydroxide, 30 mL of dioxane and 30 mL of water at 0 ° C was added 10, 34 g (34.2 mmol) of p-iodophenylsulfonyl chloride. After 15 minutes, a solution of 1.49 (37.2 mmol) sodium hydroxide in 15 mL of water was added, followed by removal of the cooling bath. After 2.0 hours, the reaction mixture is concentrated and the residue is dissolved in 300 ml of water and then washed with ethyl acetate. The aqueous solution was cooled to 0 ° C and then acidified by the addition of concentrated hydrochloric acid. The solid was collected and washed with diethyl ether to give acid (A-2) as a white solid.

»9 ··· · 9 • F" 99 • · • • 9 • · • 9 9 · • · • • • β 9 • i 9 · • 9 • • • · • 9 • · • 9 99 9 «· V • 9 * 9

¹ H NMR (300 MHz, D 2 O): δ 7.86 (d, 2H, J = 8 Hz), 7.48 (d, 2H, J = 8 Hz) 3.70 (m, 1H), 2.39 (m , 2H).

2 (S) - (4-Iodo-phenylsulfonylamino) -p-alanine (A-3)

To a stirred solution of 7.14 g (181.8 mmol) of sodium hydroxide and 40 mL of water at 0 ° C was added dropwise 1.30 mL (24.9 mmol) of bromine over 10 minutes. 9.9 g (24.9 mmol) of acid (A-2), 2.00 g (49.8 mmol) of sodium hydroxide and 35 ml of water are combined over about 5 minutes. The cooled mixture to 0 ° C was added all at once to the reaction mixture. After stirring at 0 ° C for 20 minutes, the reaction was heated to 90 ° C for 30 minutes, and then cooled to 0 ° C. The pH of the reaction mixture was adjusted to about 7 by dropwise addition of concentrated hydrochloric acid. The solid was collected, washed with ethyl acetate, and then dried in vacuo to give the acid product (A-3) as a white solid.

¹ H NMR (300 MHz, D ₂ O): δ 8.02 (d, 2H, J = 8 Hz), 7.63 (d, 2H, J = 8 Hz), 4.36 (m, 1H), 3, 51 (dd, 1H, J = 5 Hz, 13 Hz) 3.21 (m, 1H).

Ethyl 2 (S) - (4-iodo-phenylsulfonyl-amino) -β-alanine hydrochloride (A-4)

Hydrogen chloride gas was bubbled through the suspension of 4.0 g (10.81 mmol) of acid (A-3) in 50 ml of ethanol for 10 minutes at 0 ° C. Remove the cooling bath and heat the reaction to 60 ° C. After 18 hours, the reaction is concentrated to give the ester (A-4) as a white solid.

¹ H NMR (300 MHz, CD 3 OD): δ 7.98 (d, 2H, J = 8Hz), 7.63 (d, 2H,

J = 8Hz), 4.25 (q, 1H, J = 5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H),

1.01 (t, 3H, J = 7 Hz).

9999

9 9

9 <

9 9 «

99

9 9 * 99 • 9 f · 9 9 ··

9

9 9 9 9 9 · 9 9 9 9 9 • 99 999 99 99 Ethyl 4- [2- (2-aminopyridin-6-yl) ethyl] benzoate (A-5a)

A mixture of 700 mg (2.63 mmol) of A-5 ester (described in Scheme 29 of WO 95/32710, published Dec. 7, 1995), 350 mg of a 10% palladium-on-carbon solution and ethanol is stirred. at a pressure of 0.1 MPa of hydrogen. After 20 hours the reaction was filtered through a pad of celite and then concentrated to give the 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): δ 7.95 (d, 2H, J = 8Hz), 7.26 (m, 3H) 6.43 (d, 1H, J = 7 Hz), 6.35 (d, 1H, J = 8 Hz), 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 625 mg (2.31 mmol) of the ester (A-5a) in 12 mL of 6N hydrochloric acid was heated to 60 ° C. After about 20 hours, the reaction is concentrated to give acid (A-6) as a tan solid.

¹ H NMR (300 MHz, CD 3 OD): δ 7.96 (d, 2H, J = 8 Hz), 7.80 (m, 1H), 7.33 (d, 2H, J = 8 Hz), 6.84 ( d, 1H, J = 9 Hz), 6.69 (d, 1H, J = 7 Hz), 3.09 (m, 4H).

ethyl-4- [2- (2-amino-pyridin-6-yl) ethyl] benzoyl-2 (S) - (4-iodo-phenylsulfonyl-amino) -β-alanine (A-7)

A solution of 400 mg (1.43 mmol) of acid (15-6), 686 mg (1.57 mmol) of amine (A-4), 358 mg (1.86 mmol) of EDC, 252 mg (1.86 mmol) of HOBT , 632 μΙ (5.72 mmol) of NMM in 10 ml of dimethylformamide are about 20 hours

• · · ·

4 4

4/92.

spinal cord. The reaction mixture was diluted with ethyl acetate and then washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product was purified by flash column chromatography on silica eluting with ethyl acetate and then with 5% isopropanol in ethyl acetate to give the amide (A-7) as a white solid.

TLC R f = 0.4 (silica, 10% isopropanol in ethyl acetate) ¹ H NMR (300 MHz, CD 3 OD): δ 7.79 (d, 2H, J = 9Hz) 7.61 (d, 2H, J = 8Hz), 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 = 7 Hz).

4- [2- (2-Amino-pyridin-6-yl) -ethyl] -benzoyl-2 (S) - (4-iodo-phenyl-sulfonyl-amino) -β-alanine (A-8)

A solution of the ester (A-7) (200 mg, 0.3213 mmol) and 6N hydrochloric acid (30 mL) was heated to 60 ° C. After about 20 hours, the reaction mixture is concentrated. The product was purified by flash column chromatography on silica eluting with 20: 20: 1: 1 ethyl acetate / ethanol / ammonium hydroxide / water to give acid (A8) as a white solid.

TLC Rf = 0.45 (silica; ethyl acetate / ethanol / ammonium hydroxide / water = 20: 20: 1: 1).

¹ H NMR (400 MHz, DMSO-d 6): δ 8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H, J = 8Hz), 7.62 (d, 2H, J = 8 Hz), 7.48 (d, 2H, J = 8 Hz), 7.27 (m, 3H),

6.34 (d, 1H, J = 7 Hz), 6.25 (d, 1H, J = 8 Hz), 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-trimethyl-stanyl-phenyl-sulfonyl-amino-p-alanine) (A-9)

4%

A solution of 70 mg (0.1178 mMol) (A-8), 49 μΙ (0.2356 mmol) of [(CH3) ₃ Sn] _2, 5 mg triphenylphosphine palladium (Pd _{(PPh3) 4)} and Heat 7 ml of dioxane to 90 ° C. After 2 hours, the reaction mixture is concentrated and the residue is purified by preparative HPLC (Delta-Pak C ₁₈ column, 15 μΜ, 100A °, 40 x 100 mm; eluting with a solution of water in methyl cyanide 95: 5 then 5:95) to give the product trifluoroacetate. The salt was suspended in 10 mL of water, treated with 5 drops of ammonium hydroxide, and then lyophilized to give the amide (A-9) as a white solid.

¹ H (400 MHz, DMSO-d 6): δ 8.40 (m, 1H), 8.18 (d, 1H, J = 8 Hz), 7.67 (m, 5H), 7.56 (d, 2H) J = 8Hz), 7.29 (d, 2H, J = 8Hz), 6.95-7.52 (m, 2H), 6.45 (bs, 2H), 4.00 (m, 1H), 3.50 (m, 1 H), 3.33 (m, 1 H), 2.97 (m, 2 H), 2.86 (m, 2 H).

4- [2- (2-amino-pyridin-6-yl) -ethyl] -benzyl-2 (S) -4- ¹²⁵ iodo-phenyl-sulfonyl-amino-.beta.-alanine (A-10)

To a tube containing 18.5 x 10 ⁷ Bq sodium iodide (Amersham, 1MS30) was added an iodine bead (Pierce) and the mixture was stirred at room temperature for 5 minutes. Immediately after preparing a solution of 0.1 mg of product (A-9) in 0.05 ml of a 10% solution of sulfuric acid in methanol, the solution is added to a test tube containing ¹²⁵ l of iodine. After stirring at room temperature for three minutes, approximately 0.04-0.05 mL of ammonium hydroxide was added to the pH of the reaction mixture 6-7. All of the reaction mixture was transferred to a Vydac peptide-protein separation column C-18 (4.6 x 250 mm) and purified by HPLC eluting with a linear gradient by concentrating the elution solutions from a 10% acetonitrile solution (0.1% (TFA)): H ₂ O (0.1% TFA) to 90% acetonitrile (0.1% TFA): H 2 O (0.1% TFA) over 30 minutes at a flow rate of 1 mL / min. A-10) 17 minutes The radioactive fractions were separated, lyophilized and diluted with ethanol to give approximately 3.7 x 10 ⁷ Bq.

194 of the product (Α-10) which co-eluted with analytical HPLC with an authentic sample of product A-8.

Technological equipment:

Analytical and preparative HPLC was performed using a Waters model 600E solvent delivery system, a Rheodyne 7125 injector, a Waters model 990 photodiode spectral system, and a Giison FC 203 microfraction collector. Protein Vydac C-18, 4.6 x 250 mm with Brownlee modular protective column C-8. Acetonitrile was Fisher-Optima. 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 inhibit osteoclast activity, it is advisable to measure

The ability of osteoclasts to leave these resorptive wells after application of the inhibitory agent.

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). 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 7-14 days old New Zealand White Hare are removed, cleaned of soft tissues and placed in ctMEM 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 x 10 ⁷ cells / ml. A cell suspension of 5 x 10 ⁶ / ml in aMEM containing 5% fetal calf serum, nM 1.25 (OH) 2D ₃ and penicillin and streptomycin was added to the 200 x 6 mm bovine tissue sections. 200 ml of this mixture and the bone slice mixture were incubated at room temperature for 2 hours

196 ..............

° 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).

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 IC50 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 process

197 confirming the correlation between their known use and the positive results of the tests.

EIB test

Duong et al., J. Bone Miner. Res. 8, S378, 1993, describes an assay for the expression of human integrin ανβ3. It is believed that integrin stimulates the adhesion of osteoclasts to the bone matrix since anti-integrin antibodies 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.

198

SPA test

Materials:

Wheat germ agglutinin scintillation beads, SPA (Amersham).

2. Octylglucopyranoside (Calbiochem).

3. HEPES (Calbiochem).

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 are suspended in each tube

199

(40 mg / ml) pre-treated beads in 97.5 microliters of binding buffer and 20 microliters of 50-OG buffer. 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.

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 exam

200 • · 9

Φ · ·

Φ · · · ·

Cells similar to mouse osteoblasts were plated on CORNING 24-well plates 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:

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. Then * * · «· ·

201 cells were stained for tartrate-resistant acid phosphatase as follows:

The 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 violet Red Vioiet 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, the number of positively stained cells with multiple nuclei was determined in each well.

Ανβ5 binding test

Duong et al., J. Bone Miner. Res., 11: S290, 1996, describes a system for the expression of the human α-β 5 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 CaCl ₂ .

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 overnight at 4 ° C with human vitronectin (3 micrograms / ml) in 50 mM carbonate buffer pH 9.6, used.

100 microlitres of solution per well. The plates were then washed 2 times

4 ·

4 4 »

4

202

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. ανβ5-expressing cells (293) were grown in MEM in the presence of 10% fetal calf serum until a continuous layer of 90% was formed. The cell material was then separated using Trypsin / EDTA solution 1 time and the cells were washed 3 times with serum free MEM. 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 with DPBS and then incubated with the glucosaminidase substrate (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 concentration was then quantitatively determined

9 9 · 9 9 • 99 ·

9 9

203

9 9 9 9 • 9 · 9 9

9

9 9 9 9 ·

9

9 9 · · 9 9 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.

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 typically less than 100 nM in the 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 (48)

PATENT CLAIMS - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (pyridin-3-yl) -3- {2-oxo-3- [3] - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (pyridin-3-yl) - 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -4-methyl-imidazolidin-1-yl} -propionic acid , 3 (R) - (Pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -4-methyl-imidazolidin-1-yl} -propionic acid 3 (S) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-methoxypyridin-3-yl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6) -ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1- yl} -propionic acid 3 (R) - (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine) -2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, 3 (S) - (4-Methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)] 3-R (4) - (4-methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-) -propyl] -imidazolidin-1-yl} -propionic acid tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, I · · < ► · · < • · · · · < 241 3 (S) - (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) 3-R - (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-Methyl-3-oxo-3,4-dihydro-2H-2-yl) -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid benzo [1,4] oxazin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - imidazolidin-1-yl} -propionic acid 3 (R) - (4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6) -methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 - yl} -propionic acid 3 (R) - (6-methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine) 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2-fluorobiphenyl-4-yl) -3- {2-oxo-3- [3- (5,6) 7,8-tetrahydro- [1,8-naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-fluorobiphenyl-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2-oxo-2,3-dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-oxo-2,3- dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3999999 · 9 ·· · · - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (5-hydroxypyridin-3) -yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (5-hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - 2-S-benzenesulfonylamino-3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2]] -imidazolidin-1-yl} -propionic acid -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl-propyl] -imidazolidin-1-yl} -pent-4-enoic acid 3 (R) - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent-4-enoic acid 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent-4-enoic acid 3 (S) - (5-ethoxypyridin-3-yl) -3- (3- { 3- [6- (4-Methoxybenzylamino) - Pyridin-2-yl] -propyl} -2-oxo-imidazolidin-1-yl) -propionic acid 3 (R) - (5-ethoxypyridin-3-yl) -3- (3- {3- [6- (4-Methoxy-benzylamino) -pyridin-2-yl] -propyl} -2-oxo-imidazolidin-1-yl) -propionic acid 3- (5-ethoxypyridin-3-yl) -3- (3- {3- [6- (4-Methoxybenzylamino) 235] -pyridin-2-yl] -propyl} -2-oxo-imidazolidin-1-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2-oxo- imidazolidin-1-yl} -3 (S) - (5-ethoxypyridin-3-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2-oxo- imidazolidin-1-yl} -3 (R) - (5-ethoxypyridin-3-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2-oxo- imidazolidin-1-yl} -3- (5-ethoxypyridin-3-yl) -propionic acid 3 (S) - (2-oxo-2,3-dihydro-1H-oxa-1,5-diazanaphthalene-7) -yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid , 3 (R) - (2-Oxo-2,3-dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2-oxo-2,3-dihydro-1H-oxa-) 1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine -1-yl} -propionic acid 3 (S) - (2,3-dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- ( 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pr 3 (R) - (2,3-dihydro-1H-oxa-1,5-diazanaphthalen-7-yl) -3- (2-oxo-3-yl) -imidazolidin-1-yl} -propionic acid [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2,3-dihydro-1H) -oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3] 236 • · ·· - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (3-fluorobiphenyl-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2-oxo-2,3- dihydrobenzoxazol-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3-R - (2-oxo-2,3-dihydrobenzoxazol-6-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro-) -} - propionic acid 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2-oxo-2,3-dihydrobenzoxazol-6-yl) -3- (2-oxo-3) - [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-ethoxy- 3-Fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - Propionic acid 3 (R) - (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine-2- yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) - [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- &lt; / RTI &gt; 234 99,999 · 9 9 • 9 9 - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (quinolin-3-yl) -3- {2-oxo-3- [3- ( 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (quinolin-3-yl) -3- {2- oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (ethinyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (Ethinyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -propionic acid, 3- (ethynyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] 3-S (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) -imidazolidin-1-yl} -propionic acid naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyl) Din-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (Pyridin-3-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, 3- (Pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1- yl} -propionic acid 3 (S) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine) 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (6-methoxypyridin-3-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6- ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl -propionic acid, 3 (R) - (6-ethoxypyr) idin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3- (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)} -propionic acid 3-S - (4-Methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (4-Methoxyquinolin-7-yl) -3- (2-oxo) -tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (4-methoxyquinoline-7- yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl -imidazolidin-1-yl} -propionic acid, 232 in « 44 * 4 44 44 • • 4 4 4 4 · 4 * 4 • • • 4 4 4 4 4 « • • • · 4 4 4 4 • 4 4 4 44 · 4 4 4 • 4 44 3 (R) - (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)] 3- (6-Amino-pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1] -propyl] -imidazolidin-1-yl} -propionic acid 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (S) - (4-methyl-3-oxo-3,4-dihydro-2H-benzo [1, 4] oxazin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -propionic acid 3- (R) - (4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- (2-oxo- 3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (4-methyl-3-oxo) -3,4-Dihydro-2H-benzo [1,4] oxazin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) Naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5, 5-methyl-2-oxo-pyridin-3-yl)] 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (6-methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl 1] -imidazolidin-1-yl} -propionic acid 3- (6-methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2-fluorobiphenyl-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2-fluorobiphenyl-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro-44,9444) 1. Compounds antagonizing integrin receptors from the group · · »♦ *« 205 • 99 99 9 9 # 9 9 9 9 Compounds according to claim 1, of the structural formulas wherein the dotted line a represents a single or double bond, provided that in the case of a double bond the carbon atoms from which the bond is derived are substituted only by the substituents R ¹⁰ and R ¹² , X stands for Substances according to claim 2, structural formula φ »·· φφφφ φ 224 where the dashed line a represents a single or double bond, provided that in the case of a double bond, the atoms are atoms, of which the linkage originates, substituted only with R ¹⁰ and R ^12, and X is selected from the group 4 4 4 4 4 4 4 · 4 4 4 4 · 4 4 »44 4 4 4 4 · · 4 · ·· ·· 4 4 • 4 4 • 4 4 4 5 »· # ·» 233 • * 4 4 4 · 4 4 229 (C 1-8 alkyl) _p aminosulfonylaminoskupina and (arylC C8alkyl) _p aminosulfonylaminoskupina. 4 # »· · 4 4 4 4 99 4 4 445 4 «44 C 1-8 alkyl, arylC 1-6 alkyl, hydroxy, oxo, arylaminocarbonyl, arylC 1-5 alkylaminocarbonyl, aminocarbonyl and aminocarbonylC 1-6 alkyl. and R ⁴ is independently 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. 4 4 4 4 • 44 4 4 4 4 «• 4 * 445 226 4 4 4 4 4 5 4 4 4 4 4 Compound according to claim 3, structural formula The compound of claim 4, wherein X is or ♦ φ φφφφ 225 ΦΦ ·· • ♦ · · ♦ ♦ · Φ · · · · · · · · 4 «1 2 3 4 444 444 4 · 44 (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, arylC1-6alkylsulfonylaminoC1-6alkyl, 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-Oalkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) ) _p aminosulfonylaminoC 1-6 alkyl, (arylC 1-8 alkyl) _p aminosulfonylamino, 210 99999 · 9 · · 99 · 9 · 99 9 «9999 • 99 9 4 9999 4 ····· » 4> 444 4 4 · 4 44 • 4 * 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4-NR ² -NR C-NR'R or denotes a 5- or β-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, wherein the carbon nitrogen in the ring are 206 unsubstituted or substituted with one substituent R ¹ and the ring carbon atoms are unsubstituted or substituted with one or two substituents R ¹ or a 9- to 14-membered polycyclic ring system in which one or more rings is aromatic, said polycyclic the 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 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 -NR ⁴ - (CH ₂ ) _n -, - (CH ₂₎ m S- _(CH2) n-, - (CH ₂ ) _m -SO- (CH ₂ ) _n -, - (CH 2) m -SO _{2 -} (CH ₂ ) _n -, - (CH ₂₎ m O- (CH 2) n O- _(CH2) p-, - (CH2) m O- (CH ₂₎ n -NR ⁴ - (CH 2) p - (CH 2) m -NR ⁴ - (CH 2) n-NR 4 (CH 2> p - (CH ₂₎ m O- (CH ₂₎ rrS- (CH ₂ ) p - (CH ₂ ) _m -S- (CH 2) _n -S- (CH ₂ ) p -, HCH2) ^m-4 - (CH 2) ns (CH2) p - (CH 2) m -NR ⁴ - (CH 2) n O- (CH _{2) p} - (CH ₂₎ m * S- (CH2) n.- -O- (CH ₂₎ p - (CH ₂₎ m S- (CH2) n NR4. _(CH2) p - (CH2) MZ _(CH2) n- wherein Z represents a 3- to 10-membered monocyclic or a polycyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, the ring nitrogen atoms are unsubstituted or substituted by one substituent R ¹ and the ring carbon atoms are unsubstituted or substituted by one or two substituents R ¹ and besides can be any atom - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (4-Ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (5-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (5-hydroxypyridin-3) -yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid , 3 (R) - (5-Hydroxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) acid 3-S - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid yl) -propyl] -imidazolidin-1-yl} -pent-4- enoic acid 3 (R) - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -pent-4-enoic acid 3 (S) - (5-ethoxypyridin-3-yl) -3- (3- {3- [6- (4-methoxybenzylamino) -pyridin-2-yl] -propyl 2-Oxoimidazolidin-1-yl) -propionic acid 3 (R) - (5-ethoxypyridin-3-yl) -3- (3- {3- [6- (4243) -methoxybenzylamino) -pyridin-2-yl] -propyl} -2-oxoimidazolidin-1-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2-oxo -imidazolidin-1-yl} -3 (S) - (5-ethoxypyridin-3-yl) -propionic acid 3- {3- [3- (6-aminopyridin-2-yl) -propyl] -2-oxo 3-S (2) - (2-oxo-2,3-dihydro-1H-4-oxa-1) -imidazolidin-1-yl} -3 (R) - (5-ethoxypyridin-3-yl) -propionic acid 5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine- 1-yl-propionic acid 3 (R) - (2-oxo-2,3-dihydro-1H-4-oxa-1,5-diazanaphthalen-7-yl) -3- (2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-dihydro) -1H-4-oxa-1,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-one) -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydro-1H-4-oxa-1,5-diazanaphthalen-7-yl) -3- { 2-Oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3-oxo-3,4-dihydro-2 H -1-oxa-4,5-di Azanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3-R - (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3-} -propionic acid (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3-oxo-3,4) -dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine- 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 - (3-oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3,4-dihydro-2H-1-oxa-4,5-diazanaphthalene) -7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, 3 (R) - (3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6, 2-oxo-3- (2-oxo) -propionic acid] 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (3,4-dihydro-2H-1-oxa-4,5-) diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl} -propionic acid 3- (furo [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (furo [2,3-b] pyridin-6-yl) - 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, 237 • 3 (R) - (Furo [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]] - 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine- 2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (2,3-dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [ 3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (furo [3,2- b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 3-R (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) -yl} -propionic acid - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (furo [3,2-b] pyridin-6-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, 3 (S) - (2,3-Dihydro-furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [ 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrofuro [3,2-b] pyridin-6-yl) -3 - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, • · • ♦ 238 • 3- (2,3-dihydrofuro [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzimidazol-2-yl) -3- {2-oxo-3- [3- ( 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (benzimidazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (benzimidazole) -2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (1H-imidazo [4,5-c] pyridin-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro) - [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (1H-imidazo [4,5-c] pyridin-2-yl) - 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (1H-imidazo [4,5-c] pyridin-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2)] -yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzoxa) zol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl 3-R (benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionic acid] yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [ 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (1-methyl-1H-pyrazol-4-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, The compound of claim 5, wherein Y is selected from the group - (CH 2) m -O- (GH 2) n -, - (CH2) m-NB. ^4- (CH 2) n -, - (CH 2) m -S- (CH 2) m -> - (CH 2) m -SO- (CH 2) n -, - (CH 2) n SO 2 - (CH 2) m -, (CH 2) m O- (CH 2) n O- (CH 2) p -, - (CH 2) m -O- (CH 2) n -NR ⁴ - (CH 2) p -, - (CH2) m-NK ⁴ - (CH2) n-NR ⁴ - (CH2) p-, and - (CH 2) m -NR ⁴ - (CH 2) n O- (CH2) p-, wherein any carbon atom in the methylene CH ₂ group in the meaning of Y, other than ^R4, can be substituted by one or two substituents R ^3rd 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 or a 9- to 14-membered polycyclic ring system in which 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 ring nitrogen atoms are unsubstituted or substituted with one substituent R ¹ and the ring carbon atoms are unsubstituted or substituted with 1 or 2 substituents R ¹ . 7. A compound according to claim 6, wherein Y is (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 ₂ in the meaning of Y, other than R ⁴ , is optionally substituted with 1 or 2 R ³ substituents. 8 98 89 A compound according to claim 7, wherein Y is (CH ₂ ) _m or (CH ₂ ) m -NR ⁴ - (CH ₂ ) _n , wherein any carbon atom in the methylene group CH ₂ in the meaning of Y, other than R ⁴ , is optionally substituted with 1 or 2 R ³ substituents. 9 9 9 9 1 · 9 9 · 9 ♦ 9 9 9 9 999 999 999 (999) 9 (99) 3 (S) - (3,4-dihydro-2H-1-oxa-4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5, 7-oxo-2-oxo-4,5-diaza-naphthalen-7-yl)] 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3,4-dihydro-2H-1-oxa) -4,5-diazanaphthalen-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - imidazolidin-1-yl} -propionic acid 3 (S) - (furo [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7, 8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (furo [2,3-b] pyridin-6-yl) - 3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 ( S) - (2,3-Dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] 3 (R) - (2,3-Dihydrofuro [2,3-b] pyridin-6-yl) -3- {2-thiophen-2-yl] -propyl] -imidazolidin-1-yl} -propionic acid -oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - ( furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - p 3-R (furo [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6-dimethyl) -imidazolidin-1-yl} -propionic acid 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (2,3-dihydrofuro [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl } -propionová, 245 3 (R) - (2,3-Dihydrofuro [3,2-b] pyridin-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzimidazol-2-yl) -3- {2-oxo-3- [ 3- (5,6,7,8-Tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (Benzimidazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (1 H -imidazo [4,5- c] pyridin-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8]) Naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (1H-imidazo [4,5-c] pyridin-2-yl) -3- (2-oxo) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (benzoxazole- 2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - Propionic acid 3 (R) - (Benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)] -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (1-methyl-1H-pyrazole- 4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} - propionic acid 3 (R) - (1-methyl-1H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] [Naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, and pharmaceutically acceptable salts thereof. 246 • 4 · 4 · 4 4 4 4 • 44 444 444 44 44 9 9 9 9 9 9 9 9 9 9 244 • 99 99 99 98 99 9 «9 9 9 9 9 9 · · 9 9 9 · ♦ · · · f 9 9 9 9999 · · 9 · · · 99 99 999 999 ·· ·· 242 9 9 · ·· 9 9 · · · ♦ 9 9 9 9 9 99 99 9 9 9 9 9 ·· • 9 9 9 9 9 9 9 99 99 99 9 4 4 Compounds according to claim 8, wherein the substituents R ^{3 are} independently selected from hydrogen, fluorine, trifluoromethyl, aryl; 9 9 9 • 9 216 C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C = C- _(CH2) t- -6alkylaryl C1-C = C- _(CH2) t- _CH2 = CH- _(CH2) t- ,. C 1-6 alkyl-CH = CH- (CH ₂ ) _t -, 3-7-CH = CH- (CH _{2) t} -, aryl-CH = CH- _(CH2) t- C1 -6alkylaryl-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 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, • 217 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 aminosulfonylaminoC 1-6 alkyl, (arylC 1-8alkyl) _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, C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl, «· ♦ · · · 218 • (C1 -8alkyl) _p aminocarbonylC 1 -6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC -8alkyl) _p aminocarbonyl, (arylC -8alkyl) _p aminokarbonylC1-6alkyl, 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 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, arylC 1-8 alkyl, C 1-8 alkylcarbonyloxyC 1-4 alkyl, arylC 1-8 alkylcarbonyloxyC 1-4 alkyl, C 1-8 alkylaminocarbonylmethylene, C1-8dialkylaminocarbonylmethylene, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, C 1-8 alkyl, aryl, halogen, hydroxy, aminocarbonyl, C3-8cycloalkyl, aminoC1-6alkyl, (aryl) _p aminocarbonyl, hydroxycarbonyl, (arylC1-5alkyl) _p aminocarbonyl, hydroxycarbonylC1-6alkyl, arylC1-6alkyl, 219 (C1-6alkyl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p aminoC2-6alkyl, C1-8alkylsulfonyl, 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, C1-6alkylsulfonyl, arylsulfonyl, arylC1-6alkylsulfonyl, arylC1-6alkylcarbonyl, C1-6alkylthiokarbonyl, arylthiocarbonyl, arylC 6alkylthiokarbonyl, aryl- (CH ₂₎ r O- _(CH2) s-, aryl- _(CH2) rS (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} -, HCz C- (CH _{2) r,} C 1-6 alkyl-C = C- (CH ₂ ) _t -, C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C? C- (CH _{2) t} -, C 1-6 alkylaryl-C = C- (CH ₂ ) _t -, 220 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- C 1-8 alkylcarbonylamino, arylC 1-5 alkoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl, C1-6alkylcarbonyloxy, (C1-6alkyl) _p amino, aminocarbonylC1-6alkyl, C1-6alkoxy, arylC1-6alkoxy, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _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, 221 arylC 1-8 alkoxycarbonylamino, arylC1-8 alkoxycarbonylaminoC1-8alkyl, 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 -8alkyl) _p aminosulfonylaminoskupina (arylC C8alkyl) _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, 222 1-6alkylthiokarbonylaminoskupina aryl, arylC 1-6alkylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC 1-8alkyl) _p aminocarbonyl, (arylC C8alkyl) _p aminokarbonylC1-6alkyl, or R ^w and R ¹² together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from the groups N, O and S, the nitrogen atoms in the ring, they are unsubstituted or substituted by one substituent R ¹ and the carbon atoms in the ring are unsubstituted or substituted by one or two substituents R ¹ , and in addition any alkyl group R ¹⁰ , R ¹¹ , R ¹² and R ^{13 is} unsubstituted or is substituted with 1 to 3 substituents R ¹ , 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 0 to 3, t independently represents an integer from 0 to 3, v independently represents an integer from 0 to 2, as well as pharmacologically acceptable salts thereof. 9 · 9 9 9 · 999 211 "’ ·· ....... aminoC 1-6 alkyl, (aryl) _p aminocarbonyl, (arylC 1-5 alkyl) _p aminocarbonyl, hydroxycarbonylC 1-6 alkyl, C 1-8 alkyl, arylC 1-6 alkyl, (C 1-6 alkyl) _p aminoC 2-6 alkyl, (arylC 1-6 alkyl) _p aminoC 2-6 alkyl, 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, C1-10 alkyl, aryl- (CH ₂₎ r O- _(CH2) s-, 212 99 ···· 9 99 99 9 • • • 99 • • • • • 9 9 • • • 9 • • • » • 9 9 • 9 99 9 9 · «R 999 9 · • 9 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, 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) r,} 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- (CH _{2) t} -, aryl-CH = CH- _(CH2) t- C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -, 213 • · 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 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, 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. AND 214 (aryl) _p aminokarbonylaminoC1-6aikyl (arylC -8alkyl) _p aminocarbonylamino, (arylC C8alkyl) _p aminokarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8 alkyl) _p aminosulfonylaminoskupina, (C1-8 alkyl) _p aminosulfonylaminoC1-6alkyl ( aryl) _p aminosulfonylaminoC1-6alkyl (arylC -8alkyl) _p aminosulfonylaminoskupina (arylC C8alkyl) _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, 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 arylcarbonyl, pC 8 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 R ⁵ or R ⁶ alkyl is unsubstituted or substituted by 1 to 3 R ¹ substituents; · · · · · · · · · · · · · · 215, provided that the meanings of R ⁵ and R ^{6 are} selected 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- _{(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 ) _r , C 1-6 alkyl-C = C- (CH ₂ ) _t -, 9-9 9 9 9 9 9 9 9 ··· 9 9 9999 99 99 999 99 · 99 99 (arylC 1-8alkyl) _p- aminosulfonylaminoC1-6alkyl, C1-6alkylsulfonyl, C 1-6 alkylsulfonylC 1-6 alkyl, 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 6a Iky I arylthiokarbonylaminoC1-6alkyl, arylC 1-6alkylthiokarbonylaminoskupina, arylC 1-6alkylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC -8alkyl) _p aminocarbonyl, (arylC 1-8 alkyl) _p aminocarbonylC 1-6 alkyl, or form two R ³ substituents on the same carbon atom together with that atom with a carbonyl or cyclopropyl group, wherein any R ³ alkyl group is unsubstituted or substituted with 1 to 3 R ¹ substituents; provided that the substituents R ³ are chosen such that in the resulting β the compound is a carbon atom (s) to which R is attached to at most one heteroatom; R ⁴ is independently selected from hydrogen, aryl, aminocarbonyl, C3-8cycloalkyl, 9 · 9 · 9 208 • 9 · · ·· ·· 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, HCz 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} -, C1-6alkylaryl-C = C- (CH ₂₎ r, 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,} C1 -6alkylaryl-CH = CH- (CH _{2) t} -, C 1-6 alkyl-SO ₂ - (CH _{2) t} -, C1-6alkylaryl-SO ₂ (CH _{2) t} -, C 1-6 alkoxy, arylC 6 alkoxy, arylC 1-6 alkyl, (C 1-6 alkyl) _p aminoC 1-6 alkyl, (aryl) _p amino, (aryl) _p aminoC 1-6 alkyl, 209 • · 4 · 4 44 9 · 9 9 9 999 · 999 R ⁷ R ^£ XY — Ν co ₂ r ⁹ R ¹¹ θ R ⁷ R ^a Her X-Y — N ^ N CO ₂ R = R ¹³ wherein the dotted line a represents a single or double bond, provided that when a represents a double bond, the carbon atoms from which the double bond is derived can only be substituted by R ¹⁰ and R ¹² , X is selected from the group _N ' ^{R 1} NR ² A compound according to claim 9, 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 ) _t -, arylC 1-6 alkyl, 227 CH ₂ = CH- (CH _{2) t} -, and HC = C- (CH ₂ ) _t -. A compound according to claim 10, wherein R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are} independently selected from hydrogen, aryl, C 1-6 alkyl and arylC 1-6 alkyl. The compound of claim 10, wherein R ^{9 is} selected from hydrogen, methyl and ethyl. The compound of claim 12, wherein R ⁹ is hydrogen. A compound according to claim 9, 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, 228 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 C8alkyl) _p aminosulfonylaminoskupina (arylC 1-8alkyl) _p aminosulfonylaminoC1-6alkyl, C 1-6 alkylthiocarbonylamino, C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl. A compound according to claim 14, wherein 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, The compound of claim 15, wherein R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, aryl, C 1-6 alkyl and arylC 1-6 alkyl. A compound according to claim 15 wherein R ⁹ is hydrogen, methyl or ethyl. The compound of claim 17, wherein R ⁹ is hydrogen. Substances according to claim 9, from the group 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-) - tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydro-benzofuran-6-yl) -3- {2 -oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (2,3- dihydro-benzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1 -yl} -propionic acid 3 (S) - (3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3- (3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7) 3 (S) - (Quinolin-3-yl) -3- (2-oxo-3-), 8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid [3- (5,6,7,8-tetrahydro-230) Substances according to claim 19, from the group 3 (S) - (2,3-dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (2,3-dihydrobenzofuran-6-yl) -3- (2-oxo-3) - [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (R) - (3-Fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine- 1-yl} -propionic acid 3 (S) - (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine) 2-yl) -propyl] -imidazolin-1-yl} -propionic acid 3 (R) - (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7) 3 (S) - (Ethinyl) -3- {2-oxo-3- [3], 8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, 240 3 (R) - (Ethinyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidine -1-yl} -propionic acid 3 (S) - (pyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- Substances according to claim 20, from the group 3 (S) - (2,3-dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (pyridin-3-yl) -3 - {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S 1- (6-Methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - imidazolidin-1-yl} -propionic acid 3 (S) - (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-methoxyquinolin-7-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, in the form of bis (trifluoroacetate), 3 (S) - (6) -methylaminopyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1- yl} -pro pionic acid 3 (S) - (4-ethoxy-3-fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine-2- yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (furo [2,3-b] pyridin-6-yl) -3- {2-oxo-3- [3- ( 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (furo [3,2-b] pyridine) -6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionová, 247 3 (S) - (Benzimidazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - propyl] -imidazolidin-1-yl] -propionic acid 3 (S) - (benzoxazol-2-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, and pharmaceutically acceptable salts thereof. 22. A pharmaceutical composition comprising, as an active ingredient, the integrin receptor antagonists of claim 1 together with a pharmaceutically acceptable carrier. A pharmaceutical composition obtainable by mixing the integrin receptor antagonist of claim 1 together with a pharmaceutically acceptable carrier. 24. A method for producing a pharmaceutical composition comprising admixing a compound of claim 1 with a pharmaceutically acceptable carrier. 25. A pharmaceutical composition according to claim 22, further comprising an additional 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) an inhibitor of Flk-1 / KDR, FIt-1, Tck / Tie-2, or Tie-1; h) cathepsin K inhibitors; and 248 i) prenylation inhibitors, e.g., a farnesyltransferase or geranylgeranyltransferase inhibitor or a farnesyl / geranylgeranyltransferase double inhibitor, and mixtures thereof. 26. A pharmaceutical composition according to claim 25 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. 27. The pharmaceutical composition of claim 26 wherein the organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium salt trihydrate. 28. The pharmaceutical composition of claim 25 wherein the additional active agent is selected from the group consisting of: a) cytotoxic and antiproliferative substances, b) matrix metalloproteinase inhibitors, (c) inhibitors of epidermis, fibroblast or platelet-derived growth factors; (d) VEGF inhibitors; e) an inhibitor of Flk-1 / KDR, Flt-1, Tck / Tie-2, or Tie-1, and mixtures thereof. 29. A method of inducing an integrin receptor antagonist effect in a mammal, comprising administering an effective amount of the compounds of claim 1. 30. The method of claim 29, wherein the antagonist effect is on the α1β3 integrin receptor. 249 • 9 · 31. The method of claim 30, wherein said antagonizing effect is selected from the group of inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions, viral diseases, and tumor growth. 32. The method of claim 31, wherein the antagonizing effect is to inhibit bone resorption. 33. The method of claim 29, wherein the antagonist effect on the integrin receptors is an α1β5 antagonist effect. 34. The method of claim 33, wherein the inhibitory effect is selected from the group of inhibiting restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions, and tumor growth. 35. The method of claim 29, wherein the integrin receptor antagonist effect is a double effect on α1β3 / ανβ5 receptors. 36. The method of claim 35, wherein the dual antagonist effect is selected from the group consisting of inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions, viral diseases, and tumor growth. 37. The method of claim 29, wherein the antagonist effect on the integrin receptors is an antagonist effect on αν β6. ·· »· 38. The method of claim 37, wherein the antagonizing effect is selected from the group consisting of angiogenesis, inflammatory reaction and wound healing. 39. A method of inducing an integrin receptor antagonist effect in a mammal, comprising administering an effective amount of the pharmaceutical composition of claim 22. 40. 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 22. 41. A method of inhibiting bone resorption in a mammal, comprising administering an effective amount of a pharmaceutical composition of claim 22. 42. A method of inhibiting bone resorption in a mammal, comprising administering an effective amount of a pharmaceutical composition of claim 26. 43. A method of suppressing tumor growth in a mammal, comprising administering an effective amount of the pharmaceutical composition of claim 28. 44. A method of treating tumors in a mammal comprising combining the administration of the compounds of claim 1 with radiation. 44 44 239 3 (R) - (1-Methyl-1H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridine) -2-yl-propyl] -imidazolidin-1-yl} -propionic acid 3- (1-methyl-1H-pyrazol-4-yl) -3- {2-oxo-3- [3- (5 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, and pharmaceutically acceptable salts thereof. 43 4 44 4 44 44 4444 of a methylene group CH ₂ in the meaning of Y, different from R ⁴ , substituted with one or two 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, C1-3alkoxykarbonylC1-6alkyl, hydroxykarbonylC1-6alkyloxyskupina, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-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 this aluminum atom 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, ·· · • 9 44 * 444 • • • • • • • • • • • • • • • • • • • • • 4 4 4 4 4 207 44 44 45. A compound according to claim 21 selected from the group consisting of 3 (S) - (2,3-dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [ 1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid; 9999 9 9 99 9 251 ............. 3 (S) - (Quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] - 3-S (6) - (6-Methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro-) -imidazolidin-1-yl} -propionic acid [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (6-ethoxypyridin-3-yl) -3- {2-oxo-3- [ 3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid 3 (S) - (4-ethoxy-3- fluorophenyl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, as well as pharmaceutically acceptable salts thereof. The compound of claim 45 which is 3 (S) - (2,3-dihydrobenzofuran-6-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, or a pharmaceutically acceptable salt thereof. The compound of claim 45 which is 3 (S) - (6-methoxypyridin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1]) 8] naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, or a pharmaceutically acceptable salt thereof. The compound of claim 45 which is 3 (S) - (quinolin-3-yl) -3- {2-oxo-3- [3- (5,6,7,8-tetrahydro- [1,8] [Naphthyridin-2-yl) -propyl] -imidazolidin-1-yl} -propionic acid, or a pharmaceutically acceptable salt thereof.