AU724191B2 - Integrin antagonists - Google Patents

Integrin antagonists Download PDF

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AU724191B2
AU724191B2 AU40865/97A AU4086597A AU724191B2 AU 724191 B2 AU724191 B2 AU 724191B2 AU 40865/97 A AU40865/97 A AU 40865/97A AU 4086597 A AU4086597 A AU 4086597A AU 724191 B2 AU724191 B2 AU 724191B2
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alkyl
aryl
oxo
tetrahydro
naphthyridin
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AU4086597A (en
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Ben C. Askew
Paul J. Coleman
Mark E. Duggan
George D. Hartman
William F. Hoffman
John H. Hutchinson
Robert S. Meissner
Adel M. Naylor-Olsen
James J. Perkins
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9703015.9A external-priority patent/GB9703015D0/en
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Description

WO 98/08840 PCT/US97/14912 -1- TITLE OF THE INVENTION INTEGRIN ANTAGONISTS FIELD OF THE INVENTION The present invention is related to U.S. provisional applications Serial Nos. 60/047,177, filed May 20, 1997, 60/033,579, filed December 19, 1996, and 60/025,123, filed August 29, 1996, the contents of which are hereby incorporated by reference.
The present invention provides novel compounds and derivatives thereof, their synthesis, and their use as vitronectin receptor ligands. More particularly, the compounds of the present invention are cav3 antagonists, av35 antagonists or dual oav33/av5 antagonists useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
BACKGROUND OF THE INVENTION This invention relates to compounds for inhibiting bone resorption that is mediated by the action of a class of cells known as osteoclasts.
Osteoclasts are multinucleated cells of up to 400 Rm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
More specifically, osteoclasts are believed to exist in at least two physiological states. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the WO 98/08840 PCTIUS97/14912 -2migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they attach again to bone.
Integrins are transmembrane, heterodimeric, glycoproteins which interact with extracellular matrix and are involved in osteoclast attachment, activation and migration. The most abundant integrin in osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or avp3, thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to avp3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process.
There is increasing evidence to suggest that xavp3 ligands can be used effectively to inhibit osteoclast mediated bone resoption in vivo in mammals.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
WO 98/08840 PCT/US97/14912 -3- Additionally, avp3 ligands have been found to be useful in treating and/or inhibiting restenosis (recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration and angiogenesis (formation of new blood vessels). Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine, 12th ed., 1991). avp3 antagonists, which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth. (See Brooks et al., Cell, 79:1157-1164 (1994)).
Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor avp5. A monoclonal antibody for avp5 has been shown to inhibit VEGF-induced angiogenesis in rabbit corea and the chick chorioallantoic membrane model; M.C. Friedlander, et.al., Science 270, 1500-1502, 1995. Thus, compounds that antagonize avp5 are useful for treating and preventing macular degeneration, diabetic retinopathy, and tumor growth.
In addition, certain compounds of this invention antagonize both the avp3 and av35 receptors. These compounds, referred to as "dual avp3/av35 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
It is an object of the present invention to identify compounds which bind to the avp3 receptor, avp5 receptor or both the avp3 and avp5 receptors.
It is a further object of the invention to identify compounds which act as antagonists of the avp3 receptor. It is another object of the invention to identify avp3 antagonist compounds which are useful agents for inhibiting: bone resorption mediated by osteoclast cells, restenosis, atherosclerosis, inflammation, diabetic retinopathy, macular WO 98/08840 PCT/US97/14912 -4degeneration and angiogenesis in animals, preferably mammals, especially humans. Still another object of the invention is to identify avp3 antagonists which cause tumor regression and/or inhibit tumor growth in animals.
A further object of the invention is to identify avp3 antagonists useful for preventing or treating osteoporosis. An additional object of the invention is to identify oavp3 antagonists useful for treating cancer.
It has now been found that the compounds of the present invention, avp3 ligands, are useful for inhibiting bone resorption in mammals. Thus, the compounds of the present invention are useful for preventing or reducing the incidence of osteoporosis. Additionally, the avp3 ligands of the present invention are also useful for treating and/or inhibiting restenosis, diabetic retinopathy, macular degeneration, atherosclerosis and/or angiogenesis in mammals.
SUMMARY OF THE INVENTION The present invention provides a method of eliciting a vitronectin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula 0 8 R R 9 X-Y-Z-(CH 2 C-N H 1 C02R H1R R 11 wherein X is selected from N' R
NR
2
S-NR
1 2
-NRC-NR
1
R
2 -C-NR R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either WO 98/08840 PCT/US97/14912 unsubstituted or substituted on a carbon or nitrogen atom with one or more groups chosen from R 1
R
2
R
15 or R16; a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups chosen from R 1
R
2
R
1 5 or R16; Y is selected from
R
3 0 ItI
-(CH
2
)-N-(CH
2 -(CH2)rC-(CH2 0 o II II (CH2)r-C-N-(CH2)- (CH 2
)F-N-C-(CH
2 R3 R3
(CH
2
(CH
2 m -(CH 2 )rN-S(0)2- (CH 2
R
3 R 3 -(CH2)t-S(O)-(CH2) O-(CH2)- or (CH2)r-; Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system, an isoxazoline ring or an isoxazole ring; WO 98/08840 PTU9/41 PCTIUS97/14912 -6- R 1, R 2
R
4
R
5 R 1 3 R 14 R 1 5 and R 1 6 are each independently selected from hydrogen, halogen, C I- I alkyl, C3 -8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl CI-8 alkyl, amino, amino Cp.8 alkyl, C1-3 acylamino, Cl-3 acylamino CI-8 alkyl, (C 1-6 alkyl)qamino, (C 1-6 alkyl)qamino Ci -8 alkyl, C.1-4 alkoxy, Ci1-4 alkoxy Ci -6 alkyl, hydroxycarbonyl, hydroxycarbonyl. Ci1 -6 alkyl, Ci 1 3 alkoxycarbonyl, C 1 3 alkoxycarbonyl C 1-6 alkyl, hydroxycarbonyl- C 1-6 alkyloxy, hydroxy, hydroxy C 1-6 alkyl, CI1-6 alkyloxy- Ci1 -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Ci -8 alkyl-S(O)q, (C 1-8 alkyl)qamninocarbonyl, Ci -8 alkyloxycarbonylamino, (Ci -8 alkyl)qaminocarbonyloxy, oxo, (aryl C1-8 alkyl)qamnino, (aryl)qamino, aryl C1I- 8 alkylsulfonylamino or Ci1 -8 alkylsulfonylamino;
R
3 is selected from hydrogen, aryl, aryl-(CH2)p-, hydroxyl, alkoxy, aminocarbonyl, C3-8 cycloalkyl, amino Ci1 -6 alkyl, (aryl)qaminocarbonyl, (aryl CI-5 alkyl)qaminocarbonyl, hydroxycarbonyl Ci -6 alkyl, CI-8 alkyl, aryl CI-6 alkyl, (Ci1 -6 alkyl)qamino Ci1 -6 alkyl, (aryl Ci1 -6 alkyl)qamino Ci1 -6 alkyl, CI -8 alkylsulfonyl, WO 98/08840 PTU9141 PCTIUS97/14912 -7- Ci-8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci -8 alkoxycarbonyl, Ci -8 alkylcarbonyl, arylcarbonyl, aryl C1-6 alkylcarbonyl, (Ci -8 alkyl)qaminocarbonyl, amino suif onyl, Ci -8 alkylaminosulfonyl, (aryl)qaminosulfonylamino, (aryl CI-8 alkyl)qaminosulfonyl, Ci -6 alkylsulfonyl, arylsulfonyl, aryl CI-6 alkylsulfonyl, aryl C.1-6 alkylcarbonyl, C.1-6 alkyithiocarbonyl, aryithiocarbonyl, or aryl CI -6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R1 3 andRI 4
R
6
R
7
R
8
R
9 R 1 0 and R I are each independently selected from hydrogen, aryl, aryl-(CH2)p-, aryl-(CH2)n-O-(CH2)rn-, aryl-(CH2)n-S (O)q-(CH2)m-, aryl-(CH2)n-C(O)-(CH2)m-, aryl-(CH2)n-C(O)-N(R 3 aryl-(CH2)n-N(R 3 aryl-(CH2)n-N(R 3 )-(CH2)rn-, halogen, hydroxyl, Ci1 -8 alkylcarbonylamino, WO 98/08840 PTU9/41 PCTIUS97/14912 -8aryl Ci1 -5 alkoxy, Ci -5 alkoxycarbonyl, (C 1 -8 alkyl)qaminocarbonyl, Ci1 -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (Ci1 -6 alkyl)qamino, amino Ci1 -6 alkyl, arylaminocarbonyl, aryl C 1 -5 alkylaminocarbonyl, aminocarbonyl, ammnocarbonyl Ci1 -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci -6 alkyl, Ci1 -8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Cl-S alkylcarbonylamino, aryl Cl-S alkoxy, alkoxycarbonyl, aminocarbonyl, (C1-5 alkyl)qaminocarbonyl, Cl-S alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (C 1-3 alkyl)qamino, amino C 1-3 alkyl, (aryl)qaminocarbonyl, (aryl Cl-5 alkyl)qaminocarbonyl, aminocarbonyl, aminocarbonyl Ci1 -4 alkyl, hydroxycarbonyl or hydroxycarbonyl Cl1-5 alkyl, CHmC-(CH2)s-, C1-6 alky-C=-C-(CH2)s-, C3-7 cycloalkyl-C=-C-(CH2)s-, ary1-C=-C-(CH2)s-, C 1-6 alkylary1-C=-C-(CH2)s-, CH2=CH-(CH2)s-, Ci1 -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(C-2)s-, aryl-CH=CH-(CH2)s-, C 1-6 alkylaryl-CH=CH-(CH2)s-, C 1 -6 alkyl-S02-(CH2)s-, WO 98/08840 PTU9/41 PCTIUS97/14912 -9- Ci -6 atkylaryl-S02-(CH2)s-, C 1-6 alkoxy, aryl C 1-6 alkoxy, aryl C 1-6 alkyl, (Ci1 -6 alkyl)qamino Ci1 -6 alkyl, (aryl)qamino, (aryl)qamino C1-6 alkyl, (aryl Cl1-6 alkyl)qamino, (aryl Ci1 -6 alkyl)qamino Ci1 -6 alkyl, aryicarbonyloxy, aryl C1..6 alkylcarbonyloxy, (C 1 -6 alkYl)qaminocarbonyloxy, C 1 -8 alkylsulfonylammno, arylsulfonylamino, C1-8 alkylsulfonylammno C 1-6 alkyl, arylsulfonylamino Ci -6 alkyl, aryl CI -6 alkylsulfonylamino, aryl CI-6 alkylsulfonylamino Cl-6 alkyl, Ci1 -8 alkoxycarbonylamino, Ci -8 alkoxycarbonylamino Ci -8 alkyl, aryloxycarbonylamino CI -8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl Ci -8 alkoxycarbonylamino Ci -8 alkyl, Ci -8 alkylcarbonylamino, CI-8 alkylcarbonylamiino C1-6 alkyl, arylcarbonylamino Ci -6 alkyl, aryl CL-6 alkylcarbonylamino, aryl Ci -6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino CI-6 alkyl, (C 1 -8 alkYl)qaminocarbonylamino, (Ci1 -8 alkYl)qaminocarbonylamino Ci1 -6 alkyl, (aryl)qaminocarbonylarnino Ci1 -6 alkyl, (aryl Ci -8 alkYl)qaminocarbonylamino, (aryl Ci1 -8 alkyl)qaminocarbonylamino Ci1 -6 alkyl, WO 98/08840 PTU9/41 PCTIUS97/14912 aminosulfonylamino Ci -6 alkyl, (C 1-8 alkyl)qaminosulfonylamino, (Ci1 -8 alkYl)qaminosulfonylamino Ci1 -6 alkyl, (aryl)qamninosulfonylamino CI -6 alkyl, (aryl Ci1 -8 alkyl)qaminosulfonylamino, (aryl C 1 alkyl)qaminosulfonylainino C 1-6 alkyl, Ci1 -6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 alkyl, arylsulfonyl C 1.6 alkyl, aryl C1..6 alkylsulfonyl, aryl Ci -6 alkylsulfonyl Ci -6 alkyl, Ci1 -6 alkylcarbonyl, Ci -6 alkylcarbonyl CI -6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C 1-6 alkylcarbonyl C 1.-6 alkyl, CI -6 alkylthiocarbonylammno, Ci1 -6 alkylthiocarbonylaniino Ci1 -6 alkyl, aryithiocarbonylamino Ci1 -6 alkyl, aryl Ci -6 alkyithiocarbonylamino, aryl C 1 -6 alkyithiocarbonylamino C 1 -6 alkyl, (Ci1 -8 alkyl)qammnocarbonyl C1 -6 alkyl, (aryl)qaminocarbonyl Ci1 -6 alkyl, (aryl CI -8 alkyl)qaminocarbonyl, or (aryl Ci1 -8 aikyl)qaminocarbonyl Ci1 -6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and RI 4 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 1 0 and R I are attached is itself attached to no more than one heteroatom;
R
12 is selected from hydrogen, C1-8 alkyl, WO 98/08840 PCT[US97/14912 -11 aryl, aryl C1-8 alkyl, C1-8 alkylcarbonyloxy Ci-4 alkyl, aryl C1-8 alkylcarbonyloxy C1-4 alkyl, Cl-8 alkylaminocarbonylmethylene, or CI-8 dialkylaminocarbonylmethylene; m, s and t are each independently an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and the pharmaceutically acceptable salts thereof.
In one embodiment of the present invention is the method of eliciting a vitronectin antagonizing effect wherein X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 and Z is selected from WO 98/08840 PCT/US97/14912 12
R
6 R 6 NH, 6
RR
H\NN
A
4
A
4 i R 7 R 7 7 R 16 6R R7 N R 6 7R 7 R 7 R 7 4 tL~ R 4 R
R
6 6 6 R NyI R R7 10 61 N 4 R RR 7 R 6 R 6
H
WO 98/08840 PTU9/41 PCT/US97/14912 13 R 4 N 7
R
N
R6
R
6 R 7 R 4 R 6
R
7 R 4 ,orI N/
N
1 and all other variables are as defined above; and the pharmaceutically acceptable salts thereof. Preferably, Z is selected from J<o rN~ 0 -WO 98/08840 PTU9/41 PCT[US97/14912 -14-
H
-7 NI0 0 or N,,Nl/ 0 In a class of the invention is the method of eliciting a vitronectin antagonizing effect wherein the compound has the formula 0
R
X-Y-Z-
CH
2 CNWI C2 wherein X is selected from PCTIUS97/14912 WO 98/08840 PTU9/41 15
H
or
H
Y is selected from -(CH2)r- or -(CH2)m-NR 3 -(CH2)t-;
R
3 is selected from hydrogen, aryl-(CH2)p-, alkoxycarbonyl, C3-8 cycloalkyl, (aryl)qaminocarbonyl, (aryl Ci -5 alkyl)qaminocarbonyl, C1-8 alkyl, aryl C1-6 alkyl, C 1 -8 alkylsulfonyl, aryl sulfonyl, aryl Cl-6 aikylsulfonyl, Ci -8 alkoxycarbonyl, aryloxycarbonyl, aryl CI-g alkoxycarbonyl, CI -8 alkylcarbonyl, arylcarbonyl, aryl CI-6 alkylcarbonyl, (CI -8 alkyl)qaminocarbonyl, Ci1 -6 alkylsulfonyl, or aryl Cl1-6 alkylcarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 13 and R 1 4
R
4 is selected from hydrogen, Cl-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Cl-6 alkyl, C3-8 cycloheteroalkyl Cl..6 alkyl, aryl or aryl C1-8 alkyl, WO 98/08840 PTU9/41 PCT[US97/14912 -16-
R
8 is selected from hydrogen, aryl, aryl-(CH2)p-, CH=-C-(CH2)s-, CI -6 alkyl-C=-C-(CH2)s-, C3-7 cycloalkyl-C=EC-(CH2)s-, aryl-C=-C-(CH2)s-, Ci1 -6 alkylaryl-C=-C-(CH2)s-, CH2=CH-(CH2)s-, CI -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, C1-6 alkylaryl-CH=CH-(CH2)s-, CI-6 alkyl-S02-(CH2)s-, C1-6 alkylaryl-S02-(CH2)s-; and r is an integer from 0 to 3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
In a subclass of the invention is the method wherein the compound has the formula N.0 I <C R12 N N Y-Z-CH 2
CNH
wherein Z is selected from WO 98/08840 PTU9/41 PCT/US97/14912 17 rlk 0 V 0 ,or
R
8 is selected from hydrogen, -o N p0 OQn N N
N
N N
H
indoly1-(CH2)p-, CH=-C-(CH2)s-, Ci -6 alky1-C=-C-(CH2)s-, C3-7 cycloalkyl-C=-C-(CH2)s-, aryl-C=-C-(CH2)s-, Ci -6 alkylary-C=-C-(CH2)s-, CH2-CH-(CH2)s-, CI -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, Ci1 -6 alkylaryl-CH=CH-(CH2)s-, WO 98/08840 PTU9I41 PCTIUS97/14912 18 Ci1 -6 alkyl-S02-(CH2)s-, C 1-6 alkylaryl-S02-(CH2)s-; and R 1 2 is selected from hydrogen or Ci1 -8 alkyl; s is an integer from 0 to 3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
Illustrative of the invention is the method of eliciting a vitronectin antagonizing effect wherein the compound is selected from 2-Oxo-3- ,6,7 ,8-tetrahydro[ -naphthyridin-2-yl)ethyllpiperidin- 1 -y1-acetyl-3(S)-pyridin-3-y1-p-alanine ethyl ester; 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro -naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyl-3 (S)-pyridin-3-yl-fp-alanine trifluoroacetate; 2-Oxo-3 ,6,7 ,8-tetrahydro[ [1,8]-naphthyridin-2yl)ethyllpyrrolidin-1I-yl)acetyl-3 (S )-alkyny1-p -alanine ethyl ester; 2-Oxo-3(S)- ,6,7 ,8-tetrahydro[ 1 ,8]-naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl -3 (S)-alkyny1-Ip-alanine; 2-Oxo-3 ,6,7 ,8-tetrahydro [1 ,8]-naphthyridin-2-yl)ethyl] pyrrolidin-1 -yl)acetyl-3(S)-pyridin-3-y-p3-alanine ethyl ester; 2-Oxo-3(S)- ,6,7 ,8-tetrahydro[ [1,8]-naphthyridin-2yl)ethyllpyrrolidin- I -yl)acetyl-3(S)-pyridin-3 -yl-43-alanine; 2-Oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8]-naphthyridin-2yl)ethyllpyrrolidin- 1-yl)acetyl-3(S)-alkynyl-p-alanine ethyl ester; 2-Oxo-3 ,6,7,8-tetrahydro [1 ,8]-naphthyridin-2yl)ethyl]pyrrolidin-1I-yl)acetyl-3 (S)-alkynyl-3-alanine; WO 98/08840 PTU9/41 PCTIUS97/14912 -19- 2-Oxo-3 ,6,7 ,8 -tetrahydro[ -naphthyridin-2-yl)ethyl] pyrrolidin- 1-yl)acetyl-3 (S)-pyridin-3 -yl-f3-alanine ethyl ester; 2-Oxo-3 ,6,7 ,8-tetrahydro[ 1, 8]-naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl-3(S)-pyridin-3 -yl-p-alanine; Ethyl 2-oxo-3 ,6,7 ,8-tetrahydro [1 ,8]naphthyridin-2-yl)ethylitetrahydropyrimidin-lI -ylI -acetyl )-pyri din 3 -yI 0-alanine; 2-Oxo-3-[2-(5 ,6,7,8-tetrahydro[ 1,8]naphthyridin-2-yI ethyl] tetrahydropy rimi din-I1 -ylI-acetylI- 3 -pyri din- 3 -y1- P-alanine; Ethyl 2-oxo-3- ,6 ,7,8-tetrahydro[11,8]naphthyridin-2yl)ethyl]imidazolidin-1-yl-acetyl-3 (S )-pyridin-3-yl-f3-alanine; 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro[ 1,8]naphthyridin-2-yl )ethyl] imidazolidin- 1 -yl-acetyl-3(S)-pyridin-3-y1-p-alanine; Ethyl 2-oxo-3(R)-[2-(5 ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2yl)ethyllpyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-3-alanine; 2-Oxo-3 ,6,7 ,8 -tetrahydro[ I,8]naphthyridin-2yl)ethyllpyrrolidmn-l-yl)acetyl-3 (R)-(2-ethylindol-3 -yl)-j3-alanine; Ethyl I2-oxo-3(S)- ,8-tetrahydro- [1 ,8]naphthyridin-2ylmethyl)-amino] -pyrrolidin- 1-yl I-acetylamino)-3 -(S)-pyridin-3 -ylpropionic acid; 3 f 2-Oxo-3(S)- ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)amninolpyrrolidin- 1-yl )-acetylamino)-3-(S)-pyridin-3 -yl-propionic acid; 3-12- [6-Oxo-l1-(5,6,7 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3aS, 6aS)pyrrolo[3 ,4-b]pyrrol-5-yl] -acetylamnino)I-3-(S)pyridin-3-yl-propionic acid; WO 98/08840 PTU9/41 PCTIUS97/14912 3-f{ 2-[6-Oxo- 1 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3aR, 6aR)pyrrolo [3 ,4-blpyrrol-5 -yl] -acetylamino] pyridin-3 -yl-propionic acid; 2-Oxo-5(R)-methyl-3 ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyl Ipyrrolidn-1I -y1)acety1 -3 (S)-alkyny1 -alanine ethyl ester; 2-Oxo-5(R)-methyl-3 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-alkynyl-p-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5 ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyl Ipyrrolidin- 1 -yl) acetyl- 3(S) -pyri din -3 -yl P-alanine ethyl ester; 2-Oxo-5 (S)-benzyl-3(S)-[2-(5,6,7 ,8-tetrahydro[1i,8] -naphthyridin-2yl)ethyllpyrrolidin- I -yl)acetyl-3(S)-pyridin-3 -y1-Jo-alanine; (R)-Methyl-2-oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yhmethyl)-amino]pyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-fp-alanine ethyl ester; (R)-Methyl-2-oxo-3(S)-[2-(5 ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2ylmethyl)-aminolpyrrolidin- 1 -yl)acetyl-3 (S)-alkyny1-p-alanine; 3 -Dihydro-benzofuran-6-yl)-3-(2- {2-oxo-3 ,6,7 ,8tetrahydro- 1,8]naphthyridin-2-yl)-ethyl] -pyrrolidin- Il-yl 1acetylamino)-propionic acid ethyl ester; or 3 -Dihydro-benzofuran-6-yl)-3-(2- 2-oxo-3 ,6,7 ,8tetrahydro- 8 Inaphthyridin- 2-yl) -ethyl] -pyrrolidin- 1l-ylIacetylamino)-propionic acid; 3- {2-(2-Oxo-3 ,6 ,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-ethyl] pyrrolidin-1I-yl)-acetylamino 1-3 (S)-quinolin-3 -yl-propionic acid; WO 98/08840 PTU9/41 PCTIUS97/14912 21 3 -(2-(5(S)-Ethyl-2-oxo-3 ,8-tetrahydro-[ 1 ,8]naphthyridin-2yl)-ethyl] -pyrolidin- 1 -yl)-acetylamnino)-3 )-quinolin-3-yl-propionic acid trifluoroacetate; 3 6-Methyl-2-oxo-3- ,8-tetrahydro-[ 1,8]naphthyridin-2ylmethyl)-amino] -2H-pyridin- l-yI }-acetylamnino)-3 (S)-pyridin-3 -ylpropionic acid bis trifluoroacetate; or {6-Methyl-2-oxo-3- ,6,7,8-tetrahydro-[ 1,8]napthyridin-2yhnethyl)-amino] -2H-pyridin- l-yl) -acetylamino)-3 (S)-pyridin-3 -ylpropionic acid ethyl ester; and the pharmaceutically acceptable salts thereof.
Preferably, the compound is selected from 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro -naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyI-3(S)-pyridin-3-y1-p-alanine trifluoroacetate; 2-Oxo-3(S)4[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-13-alanine; 2-Oxo-3(S)- ,6,7 ,8-tetrahydro [1 ,8]-naphthyridin-2yl)ethyllpyrrolidin- I -yl)acetyl-3(S)-pyridin-3-y1-p-alanine; 2-Oxo-3(R)- ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyl]pyrrolidin- 1 -yl)acetyl-3(S)-alkynyl-3-alanine; 2-Oxo-3 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyljpyrrolidin- 1 -yl)acety1-3(S)-pyridin-3-yl-p-alanine; 2-Oxo-3- ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl }ethyl] imidazolidin- 1 -yl-acetyl-3-(S)-pyridin-3-yl-3-alanine; WO 98/08840 PTU9/41 PCT/US97/14912 22 2-Oxo-3-[2-(5 ,6,7,8-tetrahydro[ 1,8]naphthyridin-2-yl I ethyl] tetrahydropyrimidin- 1 -yl-acetyl-3 -(S)-pyridin-3-yl-p-alanine; 2-Oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro 1,8]naphthyridin-2yl)ethyllpyrrolidmn-l-yl)acetyl-3(R)-(2-ethylindol-3-yl)-3-alanine; I2-oxo-3(S)-[(5 ,6,7 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)aminolpyrrolidmn- -yli -acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-1{2-[6-Oxo- 1 ,8-tetrahydro-[ 1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3aS, 6aS)pyrrolo[3 ,4-b]pyrrol-5-yl]-acetylamino I pyridin-3 -yl-propionic acid; 3- 2-[6-Oxo- 1 ,8-tetrahydro-[ 1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3aR, 6aR)pyrrolol3 ,4-bjpyrrol-5 -yl] -acetylamino pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin- 1-yl)acetyl-3(S)-alkynyl-3-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7 ,8-tetrahydro [1 ,8]-naphthyridin-2yl)ethyl]pyrrolidin- 1-yl)acetyl-3(S)-pyridin-3 -y1-fp-alanine; (R)-Methyl-2-oxo-3(S)-[2-(5 ,6 ,7,8-tetrahydro[1,8] -naphthyridin-2ylmethyl)-aminolpyfrolidin- 1-yl)acetyl-3 (S)-alkynyl-o-alanine; or 3 (S)-(2,3-Dihydro-benzofuran-6-yl)-3 ,6,7 ,8tetrahydro- [1,8 ]naphthyridin-2-yl)-ethyl] -pyrrolidin- l-yl Iacetylamino)-propionic acid; and the pharmaceutically acceptable salts thereof.
Exemplifying the invention is the method wherein the vitronectin receptor antagonizing effect is an ocvj3 antagonizing effect.
An illustration of the invention is the method wherein the ocvP3 WO 98/08840 PCT/US97/14912 -23antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth. Preferably, the avp3 antagonizing effect is the inhibition of bone resorption.
An example of the invention is the method wherein the vitronectin receptor antagonizing effect is an avp5 antagonizing effect.
More specifically, the avp5 antagonizing effect is selected from inhibition of: restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
Illustrating the invention is the method wherein the vitronectin receptor antagonizing effect is a dual antagonizing effect. More particularly, the dual antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
In a second embodiment of the present invention is a method of eliciting an avp3 antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula 0 8 R R 9
X-Y-Z-(CH
2 C N C 002R HOR R 11 wherein X is selected from N R' NR 2 II II C-N R1 2
-NR-C-NR
1
R
2 -C-NR R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R1 and R 2 or PCT/US97/14912 WO 98/08840 -24a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 Y is selected from
R
3 1
-(CH
2 0
R
3 (C H2)- S(0)2-N- (C H 2)-
R
3 -(CH2)-S(0)q-(CH2) 0
II
(CH
2 )t-N-C-(CH 2 R3
(CH
2
(CH
2
R
3 -(CH2)r O-(CH2)-
F
or Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is selected from 0 4R O R 4 0 0 HN X N
N
N O O
O
4
R
WO 98/08840 PCTIUS97/14912 Nj 0, 0O 0 0 rl K VN> fN 1 0
H
0
NH
NY
R 4 VN0 0' i 0 R4 or
NY~
0
R
1
R
2
R
3
R
4
R
5 R1 3 and R1 4 are each independently selected from WO 98/08840 WO 9808840PCT/1JS97/14912 26 hydrogen, halogen, C I 10 alkyl, C3 -8 cycloalkyl, aryl, aryl C1-8 alkyl, ammno, amino C1-8 alkyl, C1-3 acylamino, Ci -3 acylamino Ci -8 alkyl, Ci -6 alkylamino, Ci -6 alkylamino- C1-8 alkyl, CI-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C.1-4 alkoxy, Cj..4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci1 -6 alkyl, C 1 -3 alkoxycarbonyl, CI-3 alkoxycarbonyl Ci -6 alkyl, hydroxycarbonyl- C 1-6 alkyloxy, hydroxy or hydroxy C 1-6 alkyl;
R
6
R
7
R
8
R
9 R 10 and R I are each independently selected from hydrogen, aryl, -(CH2)p-aryl, halogen, hydroxyl, C 1 -8 alkylcarbonylamino, aryl C.1-5 alkoxy, alkoxycarbonyl, aminocarbonyl, C 1 alkylaminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C 1 -6 alkylamino, amino Ci1 -6 alkyl, arylamninocarbonyl, aryl CI-5 alkylaminocarbonyl, aminocarbonyl, amninocarbonyl CI-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, Ci1 -8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, WO 98/08840 PTU9/41 PCTIUS97/14912 27 C1 -5 alkylcarbonylamino, aryl C1 -5 alkoxy, CI .5 alkoxycarbonyl, aminocarbonyl, Ci -5 alkylaminocarbonyl, Cl-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Cl..3 alkylamino, amino C1-3 alkyl, arylaminocarbonyl, aryl CI-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci .4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Ci .5 alkyl, -(CH2)s C=-CH, -(CH2)s C=C-C 1-6 alkyl, -(CH2)s C=C-C3-7 cycloalkyl, -(CH2)s C=EC-aryl, -(CH2)s C=C-C 1 -6 alkylaryl, -(CH2)s CH=CH2, -(CH2)s CH=CH C 1-6 alkyl, -(CH2)s CH=CH-C3-.7 cycloalkyl, -(CH2)s CH=CH aryl, -(CH2)s CH=CH Ci -6 alkylaryl, -(CH2)s S02CI-6 alkyl, -(CH2)s S02C 1-6 alkylaryl, C 1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, Cl1-6 alkylamino C 1-6 alkyl, arylamino, arylamino C 1 6 alkyl, aryl Cl-6 alkylamino, aryl C 1-6 alkylamino Cl1-6 alkyl, arylcarbonyloxy, aryl Ci1 -6 alkylcarbonyloxy, Ci -6 dialkylamnino, C 1-6 dialkylamino Cl1-6 alkyl, Ci -6 alkylaminocarbonyloxy, Ci1 -8 alkylsulfonylamino, Ci -8 alkylsulfonylamnino Ci -6 alkyl, WO 98/08840 PTU9/41 PCTfUS97/14912 28 arylsulfonylamino Ci1 -6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C 1-6 alkylsulfonylamino C 1-6 alkyl, Ci1 -8 alkoxycarbonylamino, CI-8 alkoxycarbonylamino CI-8 alkyl, aryloxycarbonylamino Ci -8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl Ci-g alkoxycarbonylamino Ci -8 alkyl, Ci -8 alkylcarbonylamino, C 1-8 alkylcarbonylamnino C 1-6 alkyl, arylcarbonylamino CI -6 alkyl, aryl CI -6 alkylcarbonylamino,aryl Ci -6 alkylcarbonylamino CI -6 alkyl, aminocarbonylamino C1-6 alkyl, CI -8 alkylaminocarbonylamino, Ci-8 alkylaminocarbonylamino CI-6 alkyl, arylaminocarbonylamino Ci -6 alkyl, aryl CI-g alkylaminocarbonylamino, aryl C1-8 alkylaminocarbonylamino C1-6 alkyl, aminosulfonylamino CI-6 alkyl, Ci1 -8 alkylammnosulfonylammno, Ci1 -8 alkylaminosulfonylamino C 1 -6 alkyl, arylaminosulfonylamino CI -6 alkyl, aryl Ci -8 alkylaminosulfonylamino, aryl Ci1 -8 alkylaminosulfonylamino C 1-6 alkyl, C 1 -6 alkylsulfonyl, CI -6 alkylsulfonyl C1-6 alkyl, aryisulfonyl CI -6 alkyl, aryl Ci -6 alkylsulfonyl, aryl Ci -6 alkylsulfonyl Ci -6 alkyl, Ci -6 alkylcarbonyl, Ci -6 alkylcarbonyl CI -6 alkyl, arylcarbonyl CI -6 alkyl, aryl Ci -6 alkylcarbonyl, WO 98/08840 PCT/US97/14912 -29aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, C1-8 alkylaminocarbonyl Ci-6 alkyl, arylaminocarbonyl C1-6 alkyl, aryl C1-8 alkylaminocarbonyl, or aryl C1-8 alkylaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R1 4 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 10 and R 11 are attached is itself attached to no more than one heteroatom;
R
12 is selected from hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, hydroxy, C1-8 alkoxy, aryloxy, aryl C1-6 alkoxy, Cl-8 alkylcarbonyloxy C1-4 alkoxy, aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, C1-8 alkylaminocarbonylmethyleneoxy, or C1-8 dialkylaminocarbonylmethyleneoxy; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; WO 98/08840 PCT/US97/14912 r is an integer from 0 to 6; s is an integer from 0 to 3; and t is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
In a third embodiment of the invention is a method of eliciting an oav3 antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula 0 R R 9
X-Y-Z-(CH
2 C-N- H C2R
H
oR R 11 wherein X is selected from N'R
NR
2
II
II 2 -NR-C-NRR 2 -C-NR' R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 or a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 Y is selected from WO 98/08840 PCTfUS97/14912 -31
R
3
-N-(CH
2 IiR 3
-(CH
2
)R-N-
0
II
0
-C-N-(CH
2
R
3 0
II
-N-C-(CH
2 -S(O)q-(CH 2 )7 O-(CH 2 or (CH2)- R3 Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system; preferably Z is selected from 4 R 7
R
WO 98/08840 PCT/US97/14912 -32- 4RR 6
H
N R 6 R R H 7 R R 6 4 R4 4l R R 6 R 7 R 7 RRx R R 0
R
1 R 4 2
R
4 7 5
R
1 an 7 1 ar eac ineednl seetdfo 6, R6 R6 R 4 R 4 R~s N Ni" R
R
R 7 R 4 R7 R 4 R 6 R 1, R2, R4, R5, R 13 and R 14 are each independently selected from hydrogen, halogen, C-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino- 0 C1-8 alkyl, Cl-6 dialkylamino, C1-6 dialkylamino Cl1 -8 alkyl, WO 98/08840 PTU9/41 PCTIUS97/14912 33 CI-4 alkoxy, CI-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C 1 -6 alkyl, C 1 -3 alkoxycarbonyl, C 1-3 alkoxycarbonyl Ci1 -6 alkyl, hydroxycarbonyl- Cl-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy- CI -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Ci -8 alkyl-S(O)q, CI -8 amninocarbonyl, Ci1 -8 dialkylaminocarbonyl, Cl1 -8 alkyloxycarbonylamino, Ci -g alkylaminocarbonyloxy or CI -8alkylsulfonylamino;
R
3 is selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, C 1-5 alkoxycarbonyl, aminocarbonyl, C3-8 cycloalkyl, amino C 1-6 alkyl, arylaminocarbonyl, aryl CI-5 alkylaminocarbonyl, hydroxycarbonyl CI -6 alkyl, C1-8 alkyl, aryl C1-6 alkyl, C 1 -6 alkylamino Cl1-6 alkyl, aryl CI-6 alkylamino Cl-6 alkyl, C 1-6 dialkylamino Cl1-6 alkyl, Ci1 -8 alkylsulfonyl, Ci1 -8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci-8 alkoxycarbonyl, Ci -8 alkylcarbonyl, aryicarbonyl, aryl Ci -6 alkylcarbonyl, Ci -8 alkylaminocarbonyl, -WO 98/08840 PCTIUS97/14912 34 aminosulfonyl, Ci -8 alkylaminosulfonyl, arylaminosulfonylamino, aryl C1-8 alkylaminosulfonyl, C 1-6 alkylsulfonyl, arylsulfonyl, aryl C.1-6 alkylsulfonyl, aryl C1-6 alkylcarbonyl, Ci -6 alkyithiocarbonyl, aryithiocarbonyl, or aryl C.1-6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R1 4
R
6
R
7
R
8
R
9 R 10 and R I are each independently selected from hydrogen, aryl, -(CH2)p-aryl, halogen, hydroxyl, Ci 1 -8 alkylcarbonylamino, aryl C1-5 alkoxy, C 1 -5 alkoxycarbonyl, aminocarbonyl, Ci -8 alkylaminocarbonyl, Ci -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C 1-6 alkylammno, amino Ci1 -6 alkyl, arylamninocarbonyl, aryl CI-5 alkylaminocarbonyl, aminocarbonyl, WO 98/08840 PTU9/41 PCTIVS97/14912 aminocarbonyl C 1 -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci1 -6 alkyl, Ci1 -8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, alkylcarbonylamino, aryl Ci-5 alkoxy, C 1-5 alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, Cl-5 alkylcarbonyloxy, C3 -8 cycloalkyl, oxo, amino, C 1-3 .alkylamino, amino Ci1 -3 alkyl, arylaminocarbonyl, aryl Ci-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl CI .4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Ci -5 alkyl, -(CH2)s C=ECH, -(CH2)s C=C-C1-6 alkyl, -(CH2)s C=C-C3-7 cycloalkyl, -(CH2)s C=EC-aryl, -(CH2)s C=C-C 1 -6 alkylaryl, -(CH2)s CH=CH2, -(CH2)s CH=CH C 1-6 alkyl, -(CH2)s CH=CH-C3-7 cycloalkyl, -(CH2)s CH=CH aryl, -(CH2)s CH=CH C 1 -6 alkylaryl, -(CH2)s S02C 1-6 alkyl, -(CH2)s SO2C.1-6 alkylaryl, C 1 -6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, C 1-6 alkylammno C 1-6 alkyl, arylamino, arylamino C1-6 alkyl, aryl C 1-6 alkylamino, aryl C1-6 alkylamino CI-6 alkyl, arylcarbonyloxy, aryl CI-6 alkyicarbonyloxy, WO 98/08840 WO 988840PCT/US97/14912 36 Ci1 -6 dialkylamino, C 1-6 dialkylamino Cl1-6 alkyl, CI -6 alkylaminocarbonyloxy, C I -8 alkylsulfonylamino, Ci1 -8 alkylsulfonylamino Ci1 -6 alkyl, arylsulfonylamino Ci1 -6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Ci1 -6 alkylsulfonylamino Ci1 -6 alkyl, Ci1 -8 alkoxycarbonylamino, CI-8. alkoxycarbonylamino Cl-g alkyl, aryloxycarbonylamino Ci -8 alkyl, aryl Cl-8 ailkoxycarbonylamino, aryl Ci -8 alkoxycarbonylamino C1-8 ailkyl, Ci1 -8 alkylcarbonylamino, Cl-8 alkylcarbonylamino Cl-6 alkyl, arylcarbonylamino Ci -6 alkyl, aryl Ci -6 alkylcarbonylamino, aryl Ci1 -6 alkylcarbonylamino Ci1 -6 alkyl, aminocarbonylamino Cl-6 alkyl, CI -8 alkylaminocarbonylammno, CI -8 alkylaminocarbonylamino Cl-6 ailkyl, arylaminocarbonylamino C 1-6 alkyl, aryl CI-8 alkylaminocarbonylamino, aryl CI -8 alkylaminocarbonylainino CI -6 alkyl, aiminosulfonylamino C1-6 alkyl, Cl-S alkylaminosulfonylamino, CI -8 alkylaminosulfonylamino Ci -6 alkyl, arylaminosulfonylamino Ci -6 alkyl, aryl CI-8 alkylaminosulfonylamino, aryl Ci1 -8 alkylaminosulfonylamino Ci1 -6 alkyl, Ci1 -6 alkylsulfonyl, C 1-6 alkylsulfonyl Cl1-6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Ci -6 alkylsulfonyl, WO 98/08840 PTU9/41 PCTtUS97/14912 37 aryl Ci1 -6 alkylsulfonyl Ci1 -6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl C 1-6 alkyl, arylcarbonyl CI-6 alkyl, aryl C1-6 alkylcarbonyl, aryl Cl -6 alkylcarbonyl Ci -6 alkyl, Ci -6 alkyithiocarbonylamnino, CI -6 alkyithiocarbonylamnino C1 -6 alkyl, aryithiocarbonylamino C 1-6 alkyl, aryl CI..-6 alkyithiocarbonylamino, aryl Ci1 -6 alkyithiocarbonylamino Ci1 -6 alkyl, C1-8 alkylaminocarbonyl C1-6 alkyl, arylaminocarbonyl CI -6 alkyl, aryl Ci -8 alkylaminocarbonyl, or aryl C 1-8 alkylaminocarbonyl CI1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and R 14 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 10 and R I are attached is itself attached to no more than one heteroatom; R1 2 is selected from hydrogen, C 1-8 alkyl, aryl, aryl C1-8 alkyl, hydroxy, C1-8 alkoxy, aryloxy, aryl C1-6 alkoxy, Ci1 -8 alkylcarbonyloxy Ci1 -4 alkoxy, aryl Ci1 -8 alkylcarbonyloxy Ci 1 4 alkoxy, Ci -8 alkylaminocarbonylmethyleneoxy, or Ci -8 dialkylarninocarbonylmethyleneoxy; WO 98/08840 PCTJUS97/14912 -38 m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
Illustrating the invention is the method wherein the avp3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of atherosclerosis, inflammation or inhibition of tumor growth.
Preferably, the oav3 antagonizing effect is the inhibition of bone resorption.
An illustration of the invention is a compound of the formula 0 R R 9 X-Y-Z-(CH 2 N C 2R H R R 11 wherein X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups chosen from R1, R 2
R
1 5 or R16; Y is selected from PCTIUS97/14912 WO 98/08840 39 R 3 0 0 0 -(H2i--N(C2) H 2 C H)- (CHA)- S(02 7 N- (CH 2 )7 (CH 2 f- -S(O) 2
(CH
2 )im
-(CH
2 )-S(0)q-(CH 2
(CH
2 h1- O-(0H 2 )wm or Z is a 5-11 membered aromatic or nonaromnatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatomns chosen from N, 0 and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system, an isoxazoline ring or an isoxazole ring; R 1, R 2
R
4
R
5 R 1 3 R 14 R 15 and R 1 6 are each independently selected from hydrogen, halogen, Cl-itO alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-8 alkyl, ammno, amino Ci1-8 alkyl, C 1-3 acylamnino, C 1-3 acylamino Ci1-8 alkyl, (Ci -6 alkyl)qamino, (Ci -6 alkyl)qamino Cl-8 alkyl, C1-4 alkoxy, C1-4 alkoxy CI-6 alkiyl, hydroxycarbonyl, hydroxycarbonyl Ci1-6 alkyl, C1 -3 alkoxycarbonyl, Ci1 -3 alkoxycarbonyl Ci1 -6 alkyl, hydroxycarbonyl- C 1-6 alkyloxy, hydroxy, hydroxy C 1-6 alkyl, C 1 -6 alkyloxy- C 1 -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, WO 98/08840 PCTIUS97/14912 trifluoroethoxy, Ci1 -8 alkyl-S(O)q, (C 1 -8 alkyl)qaminocarbonyl, Ci -8 alkyloxycarbonylamino, (CI -8 alkyl)qaminocarbonyloxy, oxo, (aryl C1-8 alkyl)qamino, (aryl)qamino, aryl CI-8 alkylsifonylamino or C1-8 alkylsulfonylamnino;
R
3 is selected from hydrogen, aryl, aryl-(CH2)p-, hydroxyl, C 1-5 alkoxy, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)qaminocarbonyl, (aryl Ci .5 alkyl)qaminocarbonyl, hydroxycarbonyl Cl-6 alkyl, Ci1-8 alkyl, aryl Cl-6 alkyl, (C 1 -6 alkyl)qamino C 1 -6 alkyl, (aryl C1 -6 alkyl)qamino Ci1 -6 alkyl, Ci -8 alkylsulfonyl, C 1-8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci -8 atkoxycarbonyl, C 1 -8 alkylcarbonyl, arylcarbonyl, aryl C1-6 alkylcarbonyl, (CI-g alkyl)qaminocarbonyl, aminosulfonyl, Ci1 -8 alkylaminosulfonyl, (aryl)qaminosulfonylamino, (aryl C1-8 alkyl)qaminosulfonyl, Ci1 -6 alkylsulfonyl, WO 98/08840 WO 9808840PCT1US97/14912 -41arylsulfonyl, aryl Cj -6 alkylsulfonyl, aryl C1-6 alkylcarbonyl, Ci1 -6 alkyithiocarbonyl, arylthiocarbonyl, or aryl C1-6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R1 4
R
6
R
7
R
8
R
9 R 10 and R I are each independently selected from hydrogen, aryl, aryl -(CH2)p-, aryl-(CH2)n-O-(CH2)m-, aryl-(CH2)n-S(O)q-(CH2)m-, aryl-(CH2)n-C(O)-(CH2)m-, aryl -(CH2)n-C(O)-N(R 3 aryl-(CH2)n-N(R 3 aryl -(CH2)n-N(R 3 halogen, hydroxyl, Ci -8 alkylcarbonylamino, aryl Ci1 -5 alkoxy, alkoxycarbonyl, (Ci1 -8 alkyl)qaminocarbonyl, C 1 -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (C 1 -6 alkyl)qamino, amino Ci1 -6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, -WO 98/08840 PCT/US97/14912 42 hydroxycarbonyl, hydroxycarbonyl Ci -6 alkyl, Ci-g alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, CI-5 alkylcarbonylamino, aryl CI -5 alkoxy, Ci 1.5 alkoxycarbonyl, aminocarbonyl, (C 1 -5 alkyl)qaminocarbonyl, CI-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (C1-3 alkyl)qamino, amino CI-3 alkyl, (aryl)qaminocarbonyl, (aryl C1-5 alkyl)qamninocarbonyl, aminocarbonyl, aminocarbonyl Ci -4 alkyl, hydroxycarbonyl or hydroxycarbonyl Cl1-5 alkyl, CH=-C-(CH2)s-, C1-6 alkyl-C=EC-(CH2)s-, C3-7 cycloalky-C=-C-(CH2)s-, aryl-C=-C-(CH2)s-, CI -6 alkylaryI-C=-C-(CH2)s-, CH2=CH-(CH2)s-, Ci -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, Ci1 -6 alkylaryl-CH=CH-(CH2)s-, C 1 -6 alkyl-S02-(CH2)s-, Ci1 -6 alkylaryl-S02-(CH2)s-, Ci1 -6 alkoxy, aryl CI-6 alkoxy, aryl Cl-6 alkyl, (Ci-6 alkyl)qamnino C1.6 alkyl, (aryl)qamino, (aryl)qamino C 1 -6 alkyl, (aryl C1-6 alkyl)qamino, (aryl C1..6 alkyl)qamnino CI-6 alkyl, arylcarbonyloxy, aryl C 1-6 alkylcarbonyloxy, (Ci1 -6 alkYl)qaminocarbonyloxy, WO 98/08840 PCTIUS97/14912 43 Ci1 -8 alkylsulfonylamino, arylsulfonylammno, ClI-g alkylsulfonylamino Ci1 -6 alkyl, arylsulfonylamino CI -6 alkyl, aryl CI-6 alkylsulfonylamino, aryl CI-6 alkylsulfonylamino C1-6 alkyl, Ci -8 alkoxycarbonylamnino, C1 -8 alkoxycarbonylamino C 1-8 alkyl, aryloxycarbonylamino Ci -8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl Ci1 -8 alkoxycarbonylamino Ci1 -8 alkyl, Ci -8 alkylcarbonylamino, Ci1 -8 alkylcarbonylamino Ci1 -6 alkyl, arylcarbonylamnino CI -6 alkyl, aryl C1-6 alkylcarbonylamino, aryl Ci -6 alkylcarbonylamino CI -6 alkyl, aminocarbonylamino Ci -6 alkyl, (CI -8 alkyl)qaminocarbonylamino, (Cl-8 alkyl)qaminocarbonylamiflo Ci -6 alkyl, (aryl)qaminocarbonylammno Cl-6 alkyl, (aryl Ci -8 alkYl)qaminocarbonylamino, (aryl CI-8 alkyl)qaminocarbonylamino CI -6 alkyl, amino sulfonylamino Ci -6 alkyl, (CI -S alkyl)qaminosulfonylamino, (CI -8 alkyl)qaminosulfonylamiflo Ci -6 alkyl, (aryl)qaminosulfonylamino Ci -6 alkyl, (aryl CI-8 alkyl)qaminosulfonylamino, (aryl CI-8 alkyl)qaminosulfonylamino C1-6 alkyl, Ci1 -6 alkylsulfonyl, Cl1.6 alkylsulfonyl C 1-6 alkyl, arylsulfonyl Ci -6 alkyl, aryl CI -6 alkylsulfonyl, aryl CI -6 alkylsulfonyl Ci -6 alkyl, Ci1 -6 alkylcarbonyl, WO 98/08840 PCT/US97/14912 -44- C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl CI-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino CI-6 alkyl, aryl CI-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1-8 alkyl)qaminocarbonyl C1-6 alkyl, (aryl)qaminocarbonyl CI-6 alkyl, (aryl C1-8 alkyl)qaminocarbonyl, or (aryl C1-8 alkyl)qaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R1 4 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 1 0 and R 1 1 are attached is itself attached to no more than one heteroatom; R1 2 is selected from hydrogen, C1-8 alkyl, aryl, aryl Cl-8 alkyl, C1-8 alkylcarbonyloxy C1-4 alkyl, aryl Cl-8 alkylcarbonyloxy C1-4 alkyl, C1-8 alkylaminocarbonylmethylene, or C1-8 dialkylaminocarbonylmethylene; m, s and t are each independently an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; WO 98/08840 PCTIUS97/14912 and the pharmaceutically acceptable salts thereof.
Particularly illustrative of the invention is the compound wherein Z is a 5-11 membered nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, 0 and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 and all other variables are as defined above.
Exemplifying the invention is the compound wherein Z is selected from R4/ R4 4R R 4 N/R 6 R 6 R6 6 >1 N H N N I L,N. l R R 7 R R 7 7 7
R
R 4 4 R R44 R76
R
4 7 7 4 4
R
A
R7 Rv N N PCT/US97/14912 WO 98/08840 -46- 0 4 0
R
7
R
4 ,or N/ Nj and the pharmaceutically acceptable salts thereof. Preferably Z is selected from 0 R 4 0 0 0 '0 4' 0 WO 98/08840 PCTIUS97/14912 -47-
NJ
0 0
VN*"<
0
H
\l
N/
r 0 01 YV1 0 or\ N N/ 0 WO 98/08840 WO 9808840PCTIUS97/14912 48 An example of the invention is the compound of the formula 0 11C 2R1
X-Y-Z-CH
2 CNH CO 2
R
wherein X is selected from R1 or N NS
H
Y is selected from -(CH2)r- or -(CH2)m-NR 3 -(CH2)t-;
R
3 is selected from hydrogen, aryl-(CH2)p-, Ci 1 -5 alkoxycarbonyl, C3-8 cycloallcyl, (aryl)qaminocarbonyl, (aryl Ci alkyl)qaminocarbonyl, CI1-8 alkyl, aryl. C1-6 alkyl, Ci1 -8 alkylsulfonyl, arylsulfonyl, aryl Ci -6 alkylsulfonyl, Cj -8 alkoxycarbonyl, aryloxycarbonyl, aryl CI -8 alkoxycarbonyl, Ci1 -8 alkylcarbonyl, arylcarbonyl, aryl Cl..6 alkylcarbonyl, (Ci1 -8 alkyl)qaminocarbonyl, Ci -6 alkylsulfonyl, or aryl Cp.6 alkylcarbonyl, PCTIUS97/14912 WO 98/08840 49 wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and R 14
R
4 is selected from hydrogen, Cl-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl CL-6 alkyl, aryl or aryl C1-8 alkyl,
R
8 is selected from hydrogen, aryl, aryl-(CH2)p-, CH=-C-(CH2)s-, Ci -6 alkyl-C=-C-(CH2)s-, C3-7 cycloalkyl-C=EC-(CH2)s-, aryl-C=-C-(CH2)s-, Ci1 -6 alkylary-C=-C-(CH2)s-, CH2=CH-(CH2)s-, Ci1 -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, Ci1 -6 alkylaryl-CH=CH-(CH2)s-, Ci1 -6 alkyl-S02-(CH2)s-, CI-6 alkylaryl-S02-(CH2)s-; and r is an integer from 0 to 3; wherein all other variables are as defined above; and the pharmnaceutically acceptable salts thereof.
Further illustrating the invention is the compound of the formula N N Y-Z-CH 2 CNH~K.C R1 WO 98/08840 PCTIUS97/14912 wherein Z is selected from rId 0 0 0
R
8 is selected from hydrogen, -o
F
N
-0>
I
'N 0
N
H
indolyl-(CH2)p-, CH=-C-(CH2)s-, Ci1 -6 alky-C=-C-(CH2)s-, C3-7 cycloalkyl-C=EC-(CH2)s-, aryl-C=-C-(CH2)s-, Ci1 -6 alkylaryl-C=-C-(CH2)s-, CH2--CH-(CH2)s-, Ci -6 alkyl-CH=CH-(CH2)s-, C3-.7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, WO 98/08840 PCT/US97/14912 -51 Ci1 -6 alkylaryl-CH=CH-(CH2)s-, Ci1 -6 alkyl-S02-(CH2)s-, C1-6 alkylaryl-S02-(CH2)s-; and R 1 2 is selected from hydrogen or C1 -8 alkyl; and s is an integer from 0 to 3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
Further exemplifying the invention is the compound selected from 2-Oxo-3-[2-(5,6,7 ,8-tetrahydro [1 -naphthyri din-2- yl)ethyl] piperi din- 1 -yl-acetyl-3(S)-pyridin-3-yl-p-alanine ethyl ester; 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyl-3 (S)-pyridin-3-yl-J3-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro [1 ,8]-naphthyridin-2yl)ethyllpyrrolidn- 1 -yl)acetyl-3 (S)-alkynyl-p-alanine ethyl ester; 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro [1 -naphthyridin-2yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-p-alanine; 2-Oxo-3 ,7 ,8-tetrahydro[ 1,8]-naphthyridin-2-yl)ethyl] pyrrolidin- 1-yl)acetyl-3(S)-pyridin-3 -yl-fp-alanine ethyl ester; 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1 ,8]-naphthyridin-2yl)ethyl]pyrrolidin- 1 -yl)acetyl-3(S)-pyridin-3-yl-p-alanine; 2-Oxo-3 ,6,7 ,8-tetrahydro[ 1,8]-naphthyridin-2yl)ethyllpyrrolidin- 1 -yI)acetyl-3 (S)-alkynyl-j3-alanine ethyl ester; 2-Oxo-3 t2-(5 ,6,7 ,8-tetrahydro 81-naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-alkynyl-J3-alanine; WO 98/08840 WO 9808840PCT/US97/14912 -52- 2-Oxo-3 ,6 ,7 ,8-tetrahydro -naphthyridin-2-yl)ethyl] pyrrolidin- 1 -yl)acetyl -3 -pyri din -3 -yl- 0 -alanine ethyl ester; 2-Oxo-3(R)-j2-(5 ,6,7 ,8-tetrahydro[ 1 ,8]-naphthyridin-2yl)ethyl]pyrrolidin-1 -y1)acetyl-3(S)-pyridin-3-y1-p-alanine; Ethyl 2-oxo-3-[2-(5 ,6,7 ,8-tetrahydro [1 ,8]naphthyridin-2-yl)ethyl]tetrahydropyrimidin-l-yI-acetyl-3(S)-pyridin-3-yl-p-alanine; 2-Ox o- 3 2-(5 ,6,7,8 -tetrahydro 1, ,8]naphthyri din -2-yl I ethyl] tetrahydropyrimidin-1I-yl-acetyl-3 (S )-pyridin-3 -y1-p-alanine; Ethyl 2-oxo-3-[2-(5 ,6 ,7,8-tetrahydro[ 1,8] naphthyridin-2yl)effiyljimidazolidin-l-y1-acetyl-3(S)-pyridin-3-yl-p-alanine; 2-Oxo-3- [2-(5,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl I ethyl]imidazolidin- 1-yl-acetyl-3 (S )-pyridin-3-yl- p-alanine; Ethyl 2-oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8]naphthyridin-2- 2-Oxo-3(R)- ,8-tetrahydro[ 1,8]naphthyridin-2- Ethyl ,6,7 ,8 -tetrahydro- [1 ,8]naphthyridin-2ylmethyl)-amino] -pyrrolidin- 1-yl }-acetylamino)-3 -(S)-pyridin-3 -ylpropionic acid; 3 ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)aminolpyrrolidin- 1-yl }-acetylamino)-3-(S )-pyridin-3-yl-propionic acid; .WO 98/08840 PTU9/41 PCT/US97/14912 53 3- 2-[6-Oxo- 1 ,8-tetrahydro-j 1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3aS, 6aS)pyrrolo[3 ,4-bljpyrrol-5-yl] -acetylamino pyridin-3 -yl-propionic acid; 3- {2-[6-Oxo- 1-(5,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)hexahydro-(3aR, 6aR)pyrrolo[3 ,4-b]pyrrol -5-yI] -acetylamino)}-3 pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3 ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S)-alkyny1-Jp-alanine ethyl ester; 2-Oxo-5(R)-methyl-3(S)- ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin-1 -yl)acetyl-3(S)-alkyny-3-alanine; 2-Oxo-5(S)-benzyl-3(S)- ,6,7 ,8-tetrahydro -naphthyridin-2-yl)ethyl Ipyrro lidin- 1 -yl)acetyl -3 -p yri din- 3 -yl P-al anmne ethyl ester; 2-Oxo-5(S)-benzyl-3(S)- ,8-tetrahydro [1 ,8]-naphthyridin-2yl)ethyl]pyrrolidin- 1-yl)acetyl-3(S)-pyridin-3 -y1-p-alanine; (R)-Methyl-2-oxo-3(S)-[2-(5 ,6 ,7,8-tetrahydro[1,8] -naphthyridin-2ylmethyl)-amino]pyrrolidin- 1-yI)acetyl-3 (S)-alkyny1-Jo-alanine ethyl ester; 5 (R)-Methyl-2-oxo-3(S)-[2-(5 ,6,7,8-tetrahydro -naphthyridin-2ylmethyl)-amino]pyrrolidin- 1 -y1)acety1-3(S)-alkyny1-Jp-alanine; 3 -Dihydro-benzofuran-6-yl)-3 {2-oxo-3 ,6,7 ,8 tetrahydro-[ [1,8]naphthyridin-2-yl)-ethyl] -pyrrolidin- l-yl Iacetylamnino)-propionic acid ethyl ester; or 3 -Dihydro-benzofuran-6-yl)-3-(2- {2-oxo-3 ,6,7,8tetrahydro-[ 1 ,8]naphthyridin-2-yl)-ethyl]-pyrrolidin- Il-yl I acetylamnino)-propionic acid; WO 98108840 WO 9808840PCTI'US97/14912 54 and the pharmaceutically acceptable salts thereof.
Preferably, the compound is selected from 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro[ [1,8]-naphthyridin-2-yl)ethyllpiperin- I -yl-acetyl-3 (S)-pyridin-3 -yl-p-alanine trifluoroacetate; 2-Oxo-3 ,6,7 ,8 -tetrahydro[ 1,8] -naphthyridmn-2yl)ethyllpyrrolidin- 1 -yl)acety1-3(S)-alkyny1-p-alanine; 2-Oxo-3(S)- ,6,7 ,8 -tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-pyridin-3-y-p3-alanine; 2-Oxo-3 ,6,7,8 -tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-alkynyl-p-alanine; 2-Oxo-3 ,6,7,8 -tetrahydro[ 1,8] -naphthyridin-2yl)ethyllpyrrolidin- 1 -yl)acetyl-3(S)-pyridin-3 -yl-p-alanine; 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro[ [1,8]naphthyridin-2-yli) ethyl] imidazolidin- 1 -yl-acetyl-3-(S)-pyridin-3-y1-p-alanine; 2-Oxo-3- ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl I ethyl] tetrahydropyrimidin- 1 -yl-acetyl-3 -(S)-pyridin-3-y-Jp-alanine; 2-Oxo-3(R)- ,8 -tetrahydro[ [1,8]naphthyridin-2- 3 {2-Oxo-3(S)- ,7,8-tetrahydro-[ [1,8]naphthyridin-2-ylmethyl)aminolpyrrolidin- 1-yl I-acetylamino)-3 )-pyridin-3 -yl-propionic acid; 3- [6-Oxo-l1-(5,6,7 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)hexahydro-(3aS, 6aS)pyrrolo[3 ,4-b]pyrrol-5-yl] -acetylamino)I-3-(S)pyridmn-3-yl-propionic acid; or WO 98/08840 WO 9808840PCTfUS97/14912 55 3-1{2-[6-Oxo- 1 -tetrahydro-[ [1,8]naphthyridin-2-ylmethyl)hexahydro-(3 aR, 6aR)pyrrolo [3 ,4-blpyrrol -5 -yl] -acetylammno)}-3 pyridin-3-yl-propionic acid; ,6,7 ,8-tetrahydro [1,8]-naphthyridin-2yl)ethyl]pyrrolidin- 1-yl)acetyl-3 (S)-alkynyl -f-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ [1,8]-naphthyridin-2yl)ethyllpyrrolidin-l1-yl)acetyl-3(S)-pyridin-3 -yl-p-alanine; (R)-Methyl-2-oxo-3(S)- ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2ylmethyl)-amino]pyrro lidin- 1-yl)acetyl-3 (S )-alkynyl-fo-alanine; or 3 (S)-(2,3-Dihydro-benzofuran-6-yl)-3 ,8tetrahydro- 1,8]Inaphthyridin -2-yl) -ethyl] -pyrro lidin- Il-yl 1 acetylamino)-propionic acid; and the pharmaceutically acceptable salts thereof.
An additional example of the invention is a compound of the formula o 8 R R 9
X-Y-Z-(CH
2 N02 wherein X is a 9- to 1 0-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 or 8, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R I and R 2
_I
Y is selected from WO 98/08840 PCT[S97/14912 56
R
3 0 0 I1 I ,-C-(CH2 R3 0 -S(0)q-(CH 2 -0O-(CH 2 or (CH2)-
R
3 Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is selected from
\N
O
R
4 Srl VN
N-
0 WO 98/08840 PCTIUS97/14912 57 0 N
R
I
LyNj 0 0' 0N" R- R4
H
R
N- -/N R 4 00 or <V 0 0
R
1
R
2
R
3
R
4
R
5
R
1 3 and R1 4 are each independently selected from hydrogen, halogen, Cl-bo alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1 -8 alkyl, CI-3 acylamino, C1-3 acylamino CI-8 alkyl, C1-6 alkylamino, C1-6 alkylamino- C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino Cl1 -8 alkyl, CI-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, WO 98/08840 PTU9/41 PCTIUS97/14912 58 hydroxycarbonyl Ci1 -6 alkyl, Ci 1 -3 alkoxycarbonyl, CI-3 alkoxycarbonyl CI -6 alkyl, hydroxycarbonyl- C 1-6 alkyloxy, hydroxy or hydroxy C 1-6 alkyl;
R
6
R
7
R
8
R
9 R 10 and R 1 1 are each independently selected from hydrogen, aryl, -(CH2)p-aryl, halogen, hydroxyl, Ci -8 alkylcarbonylamino, aryl C1 -5 alkoxy, alkoxycarbonyl, amninocarbonyl, C 1-8 alkylaminocarbonyl, Ci1 -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-6 alkylamino, amino C 1-6 alkyl, arylaminocarbonyl, aryl Ci-5. alkylamninocarbonyl, amninocarbonyl, aminocarbonyl CI -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci -6 alkyl, Ci -8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, C 1 -5 alkylcarbonylammno, aryl. C1 -5 alkoxy, alkoxycarbonyl, aminocarbonyl, C1-5 alkylaminocarbonyl, CI-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C 1-3 alkylamino, ammno Cl1-3 alkyl, arylaminocarbonyl, aryl CI-5 alkylaminocarbonyl, aminocarbonyl, WO 98/08840 PTU9/41 PCTIUS97/14912 59 aminocarbonyl C 1 -4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Cl-5 alkyl, -(CH2)s C=-CH, -(CH2)s C=C-C 1-6 alkyl, -(CH2)s C=C-C3-7 cycloalkyl, -(CH2)s C=-C-ary1, -(CH2)s C=C-C 1 -6 alkylaryl, -(CH2)s CH=CH2, -(CH2)s CH=CH Cl1-6 alkyl, -(CH2)s CH=CH-C3 -7 cycloalkyl, -(CH2)s CH=CH aryl, -(CH2)s CH=CH Ci -6 alkylaryl, -(CH2)s S02Cl1-6 alkyl, or -(CH2)s S02CI-6 alkylaryl; CI-6 alkoxy, aryl Ci1 -6 alkoxy, aryl Ci1 -6 alkyl, Ci1 -6 alkylamino Ci1 -6 alkyl, arylamino, arylamino CI1-6 alkyl, aryl CI-6 alkylamino, aryl Cl-6 alkylamnino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, C 1-6 dialkylamnino, CI-6 dialkylamino C1-6 alkyl, Ci -6 alkylaminocarbonyloxy, Ci1 -8 alkylsulfonylamino, Ci -8 alkylsulfonylamino Ci -6 alkyl, arylsulfonylamino Ci -6 alkyl, aryl C1-6 alkylsulfonylamino, aryl Ci1 -6 alkylsulfonylamino Ci1 -6 alkyl, Ci-8. alkoxycarbonylamino, Ci -8 alkoxycarbonylamino C1-8 alkyl, WO 98/08840 WO 9808840PCT/US97/14912- 60 aryloxycarbonylamino Ci -8 alkyl, aryl Ci1 -8 alkoxycarbonylamino, aryl Ci -8 alkoxycarbonylamino Ci -8 alkyl, Ci1 -8 alkylcarbonylamino, Ci1 -8 alkylcarbonylamino C 1-6 alkyl, arylcarbonylamino C 1 -6 alkyl, aryl C 1 -6 alkylcarbonylamino, aryl C 1 -6 alkylcarbonylamino Ci1 -6 alkyl, aminocarbonylamino C 1-6 alkyl, Ci1 -8 alkylaminocarbonylamino, CL-8 alkylaminocarbonylamino C1-6 alkyl, arylamninocarbonylamino CI -6 alkyl, aryl Cp8g alkylaminocarbonylamino, aryl C1I-g alkylaminocarbonylamino C 1 6 alkyl, aminosulfonylamino Ci1 -6 alkyl, Ci -8 alkylaminosulfonylamino, Ci1 -8 alkylaminosulfonylamino Ci1 -6 alkyl, arylaminosuifonylamino C1-6 alkyl, aryl CI -8 alkylaminosulfonylamnino, aryl CI -8 alkylaminosulfonylamino Ci1 -6 alkyl, C 1 -6 alkylsuifonyl, Ci1 -6 alkylsuifonyl C 1-6 alkyl, arylsulfonyl Ci -6 alkyl, aryl Ci1 -6 alkylsulfonyl, aryl Ci1 -6 alkylsulfonyl Ci1 -6 alkyl, Ci -6 alkylcarbonyl, C 1-6 alkylcarbonyl C 1-6 alkyl, arylcarbonyl Ci -6 alkyl, aryl CI -6 alkylcarbonyl, aryl C 1-6 alkylcarbonyl Ci1 -6 alkyl, Ci -6 aikyithiocarbonylamino, Ci1 -6 alkylthiocarbonylamnino Ci1 -6 alkyl, aryithiocarbonylamino CI -6 alkyl, aryl Ci1 -6 alkyithiocarbonylamino, WO 98/08840 PCT/US97/14912 -61 aryl C1-6 alkylthiocarbonylamino C -6 alkyl, C1-8 alkylaminocarbonyl C1-6 alkyl, arylaminocarbonyl C1-6 alkyl, aryl Cl-8 alkylaminocarbonyl, or aryl Cl-8 alkylaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
13 and R 14 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which RI 0 and R 1 1 are attached is itself attached to no more than one heteroatom;
R
1 2 is selected from hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, hydroxy, C1-8 alkoxy, aryloxy, aryl C1-6 alkoxy, C1-8 alkylcarbonyloxy C1-4 alkoxy, aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, C1-8 alkylaminocarbonylmethyleneoxy, or C1-8 dialkylaminocarbonylmethyleneoxy; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
An additional illustration of the invention is a compound of the formula WO 98/08840 PCT/US97/14912 -62- 0 8 R R 9
X-Y-Z-(CH
2 H N CO 2 R12 H 10R R 11 wherein X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R 1 and R 2 Y is selected from
R
3
R
3 0 0 -N-(CH2)7-
,-C-N-(CH
R
3 0
II
-(CH2) -S(O)q-(CH 2 -0-(CH 2 or (CH2)r- Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4
R
5
R
6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is selected from WO 98/08840 PTU9/41 PCTIUS97/14912 63
R
6
R
R 6 4
H
N
WO 98/08840 WO 9808840PCTIUS97/14912 64
R
6 RRN R
R
6 fR R 7R NRN
R
6 6 6 R 1
R
2
R
4
R
5 R 13 and R 14 are each independently selected from hydrogen, halogen, CI-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1I.-.8 alkyl, amnino, amino C 1-8 alkyl, C 1 -3 acylamino, CI-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino- C1-8 alkyl, CI-6 dialkylamino, Cl-6 dialkylamnino C1-8 alkyl, CI -4 alkoxy, Ci -4 alkoxy Ci -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci1 -6 alkyl, C 1 -3 alkoxycarbonyl, Ci -3 alkoxycarbonyl Ci -6 alkyl, hydroxycarbonyl- C1-6 alkyloxy, hydroxy, hydroxy CI-6 alkyl, C1-6 alkyloxy- Ci -6 alkyl, nitro, cyano, tnifluoromethyl, trifluoromethoxy, trifluoroethoxy, Ci1-8 alkyl-S(O)q, C1-8 aminocarbonyl, Ci1 -8 dialkylaminocarbonyl, Ci1 -8 alkyloxycarbonylamino, C.1-8 alkylaminocarbonyloxy or C1-8 alkylsulfonylamino;
R
3 is selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, WO 98/08840 PTU9/41 PCTIUS97/14912 65 Ci1 -5 alkoxycarbonyl, aminocarbonyl, C3-8 cycloalkyl, ammno CI -6 alkyl, arylaminocarbonyl, aryl Ci -5 alkylaminocarbonyl, hydroxycarbonyl CI -6 alkyl, C 1-8 alkyl, aryl C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, aryl C1-6 alkylamino C1-6 alkyl, C 1-6 dialkylamino C 1-6 alkyl, Cl-g alkylsulfonyl, Ci -8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, Ci1 -8 alkylcarbonyl, aryl carbonyl, aryl Cl-6 alkylcarbonyl, Ci1 -8 alkylaminocarbonyl, aminosulfonyl, Ci1 -8 alkylaminosulfonyl, arylaminosulfonylamino, aryl CI -8 alkylaminosulfonyl, Ci1 -6 alkylsulfonyl, arylsulfonyl, aryl Ci -6 alkylsulfonyl, aryl CI-6 alkylcarbonyl, C 1 -6 alkyithiocarbonyl, aryithiocarbonyl, or aryl Ci -6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted. or substituted with
R
1 3 and R 14 WO 98/08840 WO 9808840PCTIUS97/14912 66 R 6
R
7 RS, R 9 R 10 and R I are each independently selected from hydrogen, aryl, -(CH2)p-aryl, halogen, hydroxyl, C 1 -8 alkylcarbonylamino, aryl C 1 alkoxy, Ci1 -5 alkoxycarbonyl, aminocarbonyl, Ci -8 alkylaminocarbonyl, Ci1 -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Ci1 -6 alkylamino, amino Ci1 -6 alkyl, arylamninocarbonyl, aryl CI-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI -6 alkyl, C 1-8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, alkylcarbonylamino, aryl CI-5 alkoxy, alkoxycarbonyl, aminocarbonyl, CI-5 alkylaminocarbonyl, CI-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, CI -3 alkylamino, amino Ci.1-3 alkyl, arylaminocarbonyl, aryl Ci-5 alkylammnocarbonyl, amninocarbonyl, aminocarbonyl. C.1-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl C.1-5 alkyl, -(CH2)s C-=CH, -(CH2)s C=C-C 1-6 ailkyl, WO 98/09840 WO 9808840PCTIUS97/14912 -67- -(CH2)s C=C-C3-7 cycloalkyl, -(CH2)s C=-C-ary1, -(CH2)s C=C-C 1 -6 alkylaryl, -(CH2)s CH=CH2, -(CH2)s CH=CH C 1-6 alkyl, -(CH2)s CH=CH-C3-7 cycloalkyl, -(CH2)s CH=CH aryl, -(CH2)s CH=CH C 1 -6 alkylaryl, -(CH2)s SO2C1-6 alkyl, or -(CH2)s S02C 1-6 alkylaryl; C 1-6 alkoxy, aryl CI-6 alkoxy, aryl C1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, arylamifo, arylamino C 1-6 alkyl, aryl Ci1 -6 alkylamino, aryl Ci1 -6 alkylammno Ci1 -6 alkyl, arylcarbonyloxy, aryl CI -6 alkylcarbonyloxy, CI -6 dialkylamino, C1-6 dialkylamino C1-6 alkyl, Ci -6 alkylaminocarbonyloxy, Ci -8 alkylsulfonylamino, Ci -8 alkylsulfonylamino CI -6 alkyl, arylsulfonylamino Ci -6 alkyl, aryl C1..6 alkylsulfonylamnino, aryl CI-6 alkylsulfonylammio Cl.6 alkyl, CI -8 alkoxycarbonylamino, C1..8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylainino Ci -8 alkyl, aryl Ci..g alkoxycarbonylamino, aryl C 1.-8 alkoxycarbonylamino C I -g alkyl, Ci1 -8 alkylcarbonylamino, WO 98/08840 WO 9808840PCTIUS97/14912 68 C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino CI -6 alkyl, aryl CI -6 alkylcarbonylamino, aryl Ci1 -6 alkylcarbonylamnino Ci1 -6 alkyl, aminocarbonylamino C 1 -6 alkyl, CI -8 alkylaminocarbonylamino, CI -8 alkylaminocarbonylamino Ci -6 alkyl, arylaminocarbonylamino Ci -6 alkyl, aryl CI-g alkylamninocarbonylamino, aryl Ci1 -8 alkylaminocarbonylamino Ci1 -6 alkyl, aiminosulfonylamino Ci1 -6 alkyl, Ci1 -8 alkylaminosulfonylamino, C1-8 alkylaminosulfonylamino C1-6 alkyl, arylaminosulfonylamino Ci -6 alkyl, aryl C 1-8 alkylaminosulfonylamino, aryl C 1-8 alkylaminosulfonylamino C 1-6 alkyl, Ci1 -6 alkylsulfonyl, CI1-6 alkylsulfonyl Ci1-6 alkyl, arylsulfonyl C 1 6 alkyl, aryl Ci1 -6 alkylsulfonyl, aryl Ci1 -6 alkyl sulfonyl Ci1 -6 alkyl, Ci1 -6 alkylcarbonyl, C 1-6 alkylcarbonyl Ci1 -6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl CI1 -6 alkylcarbonyl Ci1 -6 alkyl, Ci1 -6 alkyithiocarbonylamino, C 1-6 alkyithiocarbonylamino CI1-6 alkyl, aryithiocarbonylamino Ci1 -6 alkyl, aryl CI -6 alkyithiocarbonylamino, aryl Ci1 -6 alkyithiocarbonylamino Ci1 -6 alkyl, Ci -8 alkylaminocarbonyl CI -6 alkyl, arylaminocarbonyl CI -6 alkyl, aryl Ci -8 alkylaminocarbonyl, or WO 98/08840 PCT/~S97/14912 -69aryl C1-8 alkylaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with
R
1 3 and R 14 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 10 and R 1 1 are attached is itself attached to no more than one heteroatom;
R
1 2 is selected from hydrogen, Cl-8 alkyl, aryl, aryl C1-8 alkyl, hydroxy, C1-8 alkoxy, aryloxy, aryl C1-6 alkoxy, Cl-8 alkylcarbonyloxy C1-4 alkoxy, aryl C1-8 alkylcarbonyloxy C1-4 alkoxy, C1-8 alkylaminocarbonylmethyleneoxy, or C1-8 dialkylaminocarbonylmethyleneoxy; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
More particularly illustrating the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a WO 98/08840 PCTIUS97/14912 pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of a vitronectin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above. Preferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, cancer and tumor growth. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.
More specifically exemplifying the invention is a method of eliciting a vitronectin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. Preferably, the vitronectin antagonizing effect is an avp3 antagonizing effect; more specifically the avp3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation or inhibition of tumor growth.
Most preferably, the avp3 antagonizing effect is inhibition of bone resorption. Alternatively, the vitronectin antagonizing effect is an antagonizing effect or a dual avp3/avp5 antagonizing effect. Examples of avp5 antagonizing effects are inhibition of: restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth. Examples of dual antagonizing effects are inhibition of: bone resorption, restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to WO 98/08840 PCTIUS97/14912 -71 the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions decribed above.
Further exemplifying the invention is any of the compositions described above, further comprising a therapeutically effective amount of a second bone resorption inhibitor; preferably, the second bone resorption inhibitor is alendronate.
More particularly illustrating the invention is any of the methods of treating and/or preventing osteoporosis and/or of inhibiting bone resoption described above, wherein the compound is administered in combination with a second bone resorption inhibitor; preferably, the second bone resorption inhibitor is alendronate.
Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of: bone resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation and/or angiogenesis.
Additional illustrations of the invention are methods of treating tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound described above and one or more agents known to be cytotoxic or antiproliferative, taxol and doxorubicin.
WO 98/08840 PCT/US97/14912 -72- DETAILED DESCRIPTION OF THE INVENTION Representative compounds of the present invention are integrin antagonists which display submicromolar affinity for the human (xv33 receptor. Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.
Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
The compounds of the present invention are administered in dosages effective to antagonize the avp3 receptor where such treatment is needed, as, for example, in the prevention or treatment of osteoporosis. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include WO 98/08840 PCT/US97/14912 -73 alkali metal salts, sodium or potassium salts; alkaline earth metal salts, calcium or magnesium salts; and salts formed with suitable organic ligands, quaternary ammonium salts.
The compounds of the present invention, may have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
The term "vitronectin receptor antagonist," as used herein, refers to a compound which binds to and antagonizes either the av[3 receptor or the avP5 receptor, or a compound which binds to and WO 98/08840 PCT/US97/14912 -74antagonizes both the avp3 and av[5 receptors a dual oav33/av5 receptor antagonist).
The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone.
The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
The term "cycloheteroalkyl," as used herein, shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two heteroatoms chosen from N, O or S. Examples of cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.
The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified alkoxy), or any number within this range methoxy, ethoxy, etc.).
The term "aryl," as used herein, refers to a monocyclic or polycyclic system composed of 5- and 6-membered fully unsaturated or partially unsaturated rings, such that the system comprises at least one fully unsaturated ring, wherein the rings contain 0, 1, 2, 3 or 4 heteroatoms chosen from N, O or S, and either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, CI-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, WO 98/08840 PCT/US97/14912 amino, amino Ci-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino-C 1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, Ci-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl Ci1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Cl-O10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, CI-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino-C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI-6 alkyl, alkoxycarbonyl, CI-3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl CI- 6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or C1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-, tri- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is unsubstituted, mono-, di- or tri-substituted with one to three of the above-named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent aryl CO-8 alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms C1-10) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. The CO-m or CI-m designation where WO 98/08840 PCT/US97/14912 -76m may be an integer from 1-10 or 2-10 respectively refers to the alkyl component of the arylalkyl or alkylaryl unit. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
When substituent R 1
R
2
R
3
R
4
R
5
R
6
R
7
R
8
R
9
R
1 1, R 1 2
R
1 3 or R 14 includes the definition CO aryl CO-8 alkyl), the group modified by CO is not present in the substituent.
Similarly, when any of the variables m, q, r or s is zero, then the group modified by the variable is not present; for example, when s is zero, the group "-(CH2)s C=CH" is In addition, the substituent "(C1-6 alkyl)qamino" where q is zero, one or two, refers to an amino, C1-6 alkylamino and C1-6 dialkylamino group, respectively. When a C1-6 dialkylamino substituent is intended, the C1-6 alkyl groups can be the same dimethylamino) or different N(CH3)(CH2CH3)).
Similarly, the substituent "(aryl)qamino" or ["(aryl Cl-6 alkyl)qamino"], where q is zero, one or two, refers to an amino, arylamino and diarylamino group, [or an amino, aryl Cl-6 alkylamino or di-(aryl C1-6 alkyl)amino] respectively, where the aryl [or aryl C1-6 alkyl] groups in a diarylamino [or di-(aryl C1-6 alkyl)amino] substituent can be the same or different.
The term "halogen" shall include iodine, bromine, chlorine and fluorine.
The term "oxy" means an oxygen atom. The term "thio" means a sulfur atom. The term "oxo" shall mean =0.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
WO 98/08840 PCT/US97/14912 -77 Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to 0
II
-C1- 6 alkyl-NH-C-C1.5 alkyl The present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents used in the treatment of osteoporosis such as bisphosphonate bone resorption inhibitors; preferably, the bone resorption inhibitor is the bisphosphonate alendronate, now sold as FOSAMAX®. Preferred combinations are simultaneous or alternating treatments of an otvp3 receptor antagonist of the present invention and FOSAMAX®.
In addition, the integrin (axvp3) antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions. These diseases include: osteoporosis (including estrogen deficiency, immobilization, glucocorticoid induced and senile), osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany. Increased bone WO 98/08840 PCT/US97/14912 -78 resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment. Similarly, the present invention would be useful in increasing bone mass in patients with growth hormone deficiency.
Thus, preferred combinations are simultaneous or alternating treatments of an oxv33 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising FOSAMAX®.
In addition, the vitronectin receptor antagonist compounds of the present invention may be effectively administered in combination with one or more agents known to be cytoxic or antiproliferative, e.g, taxol and doxorubicin.
In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating cvP3 related conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosis.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions.
Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical ocular eyedrop), subcutaneous, WO 98/08840 PCTIS97/14912 -79intramuscular or transdermal patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an avP3 inhibitor.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of 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 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage WO 98/08840 PCTfUS97/14912 administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the WO 98/08840 PCT/US97/14912 81 compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
In the schemes and examples below, various reagent symbols and abbreviations have the following meanings: AcOH: BH3*DMS: BOC(Boc):
BOP:
CBZ(Cbz):
CDI:
CH2Cl 2 CHCl 3
DEAD:
DIAD:
DIBAH or
DIBAL-H:
DIPEA:
DMAP:
DME:
DMF:
DMSO:
DPFN:
Acetic acid.
Borane*dimethylsulfide.
t-Butyloxycarbonyl.
Benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
Carbobenzyloxy or benzyloxycarbonyl.
Carbonyldiimidazole.
Methylene chloride.
Chloroform.
Diethyl azodicarboxylate.
Diisopropyl azodicarboxylate.
Diisobutylaluminum hydride.
Diisopropylethylamine.
4-Dimethylaminopyridine.
1,2-Dimethoxyethane.
Dimethylformamide.
Dimethylsulfoxide.
3,5-Dimethyl-1 -pyrazolylformnamidine nitrate.
WO 98/08840 PCT/US97/14912 82-
EDC:
EtOAc: EtOH: HOAc:
HOAT:
HOBT:
LDA:
MeOH: NEt3:
NMM:
PCA-HCl: Pd/C: Ph: pTSA
TEA:
TFA:
THF:
TLC:
TMEDA:
TMS:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide.
Ethyl acetate.
Ethanol.
Acetic acid.
1-Hydroxy-7-azabenzotriazole 1 -Hydroxybenzotriazole.
Lithium diisopropylamide.
Methanol.
Triethylamine.
N-methylmorpholine.
Pyrazole carboxamidine hydrochloride.
Palladium on activated carbon catalyst.
Phenyl.
p-Toluene sulfonic acid.
Triethylamine.
Trifluoroacetic acid.
Tetrahydrofuran.
Thin Layer Chromatography.
N,N,N',N'-Tetramethylethylenediamine.
Trimethylsilyl.
The novel compounds of the present invention were prepared according to the procedure of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The most preferred compounds of the invention are any or all of those specifically set forth in these examples.
These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
WO 98/08840 PCT/US97/14912 83 The following Schemes and Examples describe procedures for making representative compounds of the present invention.
Moreover, by utilizing the procedures described in detail in PCT International Application Publication Nos. W095/32710, published 7 December 1995, and W095/17397, published 29 June 1995, in conjunction with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
More specifically, procedures for preparing the N-terminus of the compounds of the present invention are described in WO 95/32710. Additionally, for a general review describing the synthesis of P-alanines which can be utilized as the C-terminus of the compounds of the present invention, see Cole, Recent Stereoselective Synthetic Approaches to P-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi, E, et al., Enantioselective Synthesis of P-Amino Acids, Aldrichemica Acta, 1994, 27, 3. In particular, synthesis of the 3-methyl P-alanine is taught in Duggan, M.F. et al., J. Med. Chem., 1995, 38, 3332-3341; the 3-ethynyl P-alanine is taught in Zablocki, et al., J.
Med. Chem., 1995, 38, 2378-2394; the 3-pyrid-3-yl P-alanine is taught in Rico, J.G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2amino and 2-toslylamino 3-alanines are taught in Xue, C-B, et al., Biorg. Med. Chem. Letts., 1996, 6, 339-344.
.WO 98/08840 PTU9/41 PCTIUS97/14912 -84 SCHEME 1 0 N
TMS
'-I
1-2 0 LIDA, TMEDA, THF, -78-C 0 0
NH
1-3 L-proline, ethanol, reflux NaN(TMS) 2
DMF,
ethyl bromoacetate ,-IN 11'C0 2 Et WO 98/08840 PTU9/41 PCTfUS97/14912 85 SCHEME 1 (CONTD) Co 2 Et Pd/C, EtOAc, H 2 I CO2 1-7, R =Et 6
C
l-8,R=H )6HC 1-9 BOP, NMM, CH 3
CN
0 CO2R
H
1-10, R Et\ 1-1R=) 6N HCI WO 98/08840 PCT/US97/14912 86 2-Oxo-3-(3-oxobutyl)piperidine (1-3) A stirred solution of TMEDA (3.0 g, 20 mmol), 0.5 M LDA (6 mL, in THF), and THF (10 mL) at -78 0 C was treated with 1-1 (1.7 g, 10 mmol) (for preparation, see: JOC, 1990, 55, 3682) to effect an orange solution.
After 1 h, the iodide 1-2 (2.4 g, 10 mmol) Org. Chem., 1983, 48, 5381) was added to the orange solution and the resulting solution stirred for 2 h at -78 0 C, 3 h at -15°C and then 16 h at ambient temperature. The reaction mixture was concentrated and then treated with IN HCI (30 mL). The mixture was then basified with IN NaOH/brine followed by extraction with EtOAc The combined extracts were dried (MgS04) and concentrated to give a yellow oil.
Flash chromatography (silica, EtOAc 10% CH30H/EtOAc) gave 1-3 as a colorless solid.
TLC Rf 0.42 (silica, 10% 1 H NMR (300 MHz, CDC13) 8 5.75 (bs, 1H), 3.28 2H), 2.64 (t, 7Hz, 2H), 2.30-1.50 7H), 2.16 3H).
1,81-naphthvridin-2-vl)ethyllpiperidine A solution of 1-3 (0.25 g, 1.5 mmol), L-proline (85 mg, 0.75 mmol), 1-4 (0.18 g, 1.5 mmol) (for preparation see: Synth.
Commun. 1987, 17, 1695), and ethanol (10 mL) was refluxed for 24 hr.
The cooled solution was concentrated and the residue purified by flash chromatography (silica, EtOAc 20% CH30H/EtOAc) to give 1-5 as a solid.
TLC Rf 0.32 (silica, 20% 1 H NMR (300 MHz, CDC13) 5 9.08 1H), 8.16 1H), 8.10 (d, J=8Hz, 1H), 7.50 J=8Hz, IH), 7.45 1H), 5.64 (bs, 1H), 3.31 (m, 2H), 3.18 2H), 2.50-1.60 7H).
Ethyl 2-Oxo-3-[2-([1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetate (1-6) A solution of 1-5 (0.28 g, 1.1 mmol) and DMF (10 mL) at was treated with NaN(TMS)2 (1.2 mL, 1.2 mmol, IM in hexanes) WO 98/08840 PCTIUS97/14912 87 to give a red solution. After 30 min, the red solution was treated with ethyl bromoacetate (128 iL, 1.2 mmol), followed by continued stirring for 1 h. The reaction mixture was then quenched with sat. NH4C1 and then extracted with EtOAc The combined extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% CH30H/EtOAc) gave 1-6 as a yellow gum.
TLC Rf 0.50 (silica, 10% 1 H NMR (300 MHz, CDC13) 8 9.07 1H), 8.16 1H), 8.10 (d, J=8Hz, 1H), 7.50 J=8Hz, 1H), 7.44 1H), 4.30-3.90 4H), 3.50-3.30 2H), 3.17 2H), 2.46 2H), 2.20-1.70 5H), 1.28 J=7Hz, 3H).
Ethyl 2-Oxo-3-[2-(5,6,7,8-tetrahydro-[ 1,8]-naphthyridin-2yl)ethyllpiperidin-1 -yl-acetate (1-7) A mixture of 1-6 (102 mg, 0.3 mmol), 10% Pd/C (50 mg), and EtOAc (25 mL) was stirred under a hydrogen atmosphere (1 atm) for 24 h. The catalyst was then removed by filtration through celite and the filtrate concentrated. Flash chromatography (silica, gave 1-7 as a yellow gum.
TLC Rf 0.45 (silica, 30% 1 H NMR (300 MHz, CDC13) 87.05 J=6Hz, 1H), 6.41 J=6Hz, 1H), 4.80 (bs, 1H), 4.18 J=7Hz, 2H), 4.08 2H), 3.37 4H), 2.80-1.60 13H), 1.26 7Hz, 3H).
2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin- 1-yl-acetic acid (1-8) A solution of 1-7 (71 mg, 0.21 mmol) and 6N HCI (15 mL) was stirred at 55 0 C for 2h, followed by concentration to give 1-8 as a pale yellow gum.
TLC Rf 0.09 (silica, 20% WO 98/08840 PTU9/41 PCTIUS97/14912 88 2-Oxo-3-[2-(5 ,6,7,8-tetrahydro-[ 1,8]-naphthyridin-2-yl)ethyllpiper-idin- 1 -yl-acetyl -3 (S)-pvyridin-3-yl-D-alanine ethyl ester (1-1 0) A stirred mixture of 1-8 (71 mrg, 0.20 nimol), 1-9 (59 mg, 0.22 mmol) (Rico et al., J. Org. Chem., 1993, 58, 7948), NMM (88 JIL, 0.8 mmol), and CH3CN (25 mL) was treated with BOP (97 mg, 0.22 mmol). After 24h, the reaction mixture was concentrated to dryness, dissolved in EtOAc, and then washed with H20, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% (NH3IEtOHIEtOAc) gave 1-10 as a colorless gum.
TLC Rf 0.9 (silica, 10% (N1-3IEtOH)IEtOAc) I H NMR (300 MHz, CD3OD) 8 8.55 (in, 111), 8.43 (in, IH), 7.83 (in, lH), 7.40 (mn, lH), 7.11 (in, 1H), 6.37 (in, 1H), 5.38 (in, lH), 4.08 (q, J=7Hz, 211), 4.00 (in, 2H), 3.37 (in, 4H), 2.90 (in, 1H), 2.70-1.60 (in, 1411), 1.14 J=7Hz, 3H).
2-Oxo-3- ,6,7,8-tetrahydro- [1 ,8]-naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyl-3(S)-p2yridin-3 -yl-o-alanine trifluoroacetate 01- 11') A stirred solution of 1- 11 (52 mg, 0. 10 mmol) and 6N HCl mL) was heated at 55 0 C for 2 h, followed by concentration.
Preparative HPLC (VYDAC C 18 semiprep column, gradient elution: [95:5 (0.1 TFAII-20/0.1 TFA/CH3CN) to 50:50 1 TFAIH2O/0. 1 TFA/CH3CN) 80 min] gave 1 -11 as a colorless solid.
JH NMR (300 MHz, CD3OD) 8 8.90 1H), 8.74 J=511z, 1H1), 8.61 J=8Hz, 111), 8.03 (in, 111), 7.56 J=7Hz, 111), 6.59 J=7Hz, 111), 5.43 (in, 1H), 4.03 (in, 211), 3.40 (mn, 511), 3.00 (in, 211), 2.78 (in, 411), 2.40-1.60 (in, 1211).
WO 98/08840 PTU9/41 PCTIUS97/14912 89 SCIHEME 2 Ph 1 LDA, THF, -78-C 0 1-2 44-ditert-butylbiphenyl, Li THF, 78-C 00 0
NH
2-3 INaN(TMS) 2 THF, 780C, ethyl bromoacetate pTSA, acetone, ref lux N CO 2 Et WO 98/08840 WO 9808840PCT[US97/14912 90 SCHEME 2 (CONT'D) 'CN CO 2 Et Sproline, ethanol, reflux Pd/C, H 2 ethanol N CO 2 Et 6N HO!, 5000 HCI -WO 98/08840 -WO 988840PCTIUS97/14912 91 SCHEME 2 (CONT'D)
R
HCl.H2 N -~C02!Et 2-9, R= -C=ECH 2-10, R= 3-pyridyl BOP, NMM,
CH
3
CN
0
H
N ~Ny''-C 2 Et 0OR 2-11, R =-C=-CH 2-12, R= 3-pyridyl I 1N NaOH, ethanol 0
H
N--6 N yN Y.-C 2
H
O R 2-13, R -CE=CH 2-14, R= 3-pyridyl SWO 98/08840 PCTIUS97/14912 -92- (2-Oxo-3-(3-(ethvlendioxy)butyl)pyrrolidin-1 -yl)benzyl (2-2) To a stirred solution of 2-1 (5.3 g, 30 mmol) and THF (100 mL) at -78 0 C was added LDA (17.5 mL, 35 mmol, 2.0 M in hexanes) dropwise over a 10 minute period. After 30 min, 1-2 (5.0 g, 21 mmol) was added followed by removal of the cooling bath. After 1 h, the reaction was quenched with AcOH (10 mL) and then diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 2-2 as an oil.
TLC Rf 0.38 (silica, EtOAc) 1 H NMR (300 MHz, CDC13) 8 7.25 5H), 4.48 J=15Hz, 1H), 4.40 J=15Hz, 1H), 3.94 4H), 3.18 2H), 2.44 1H), 2.30-1.30 9H).
2-Oxo-3-(3-(ethylendioxy)butyl)pyrrolidine (2-3) To a stirred solution of 2-2 (4.1 g, 14.2 mmol) in THF (100 mL) at -78 0 C was added a solution of Li 4,4'-di-tert-butylbiphenyl (188 mL, 0.5 M in THF) in 4 portions. After 1 h, the reaction was quenched with AcOH (25 mL). The resulting mixture was diluted with EtOAc and then washed with H20, sat. NaHCO3, and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc CH30H/EtOAc) gave 2-3 as a yellow oil.
TLC Rf 0.1 (silica, EtOAc) 1 H NMR (300 MHz, CDC13) 8 6.23 (bs, 1H), 3.94 4H), 3.30 (m, 2H), 2.70 2H), 2.10-1.30 9H).
Ethyl (2-Oxo-3-(3-(ethvlendioxy)butyl)pyrrolidin-l-yl)acetate (2-4) To a rapidly stirred solution of 2-3 (0.86 g, 4.3 mmol) and THF (25 mL) at -78 0 C was added NaN(TMS)2 (5.2 mL, 5.2 mmol, 1.0 M in THF). After 20 min, ethyl bromoacetate (0.58 mL, 5.2 mmol) was added followed by removal of the cooling bath. After 1 h, the reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-4 as a yellow oil.
WO 98/08840 PCT/US97/14912 -93 TLC Rf 0.53 (silica, EtOAc) 1 H NMR (300 MHz, CDC13) 8 4.18 J=7Hz, 2H), 4.04 2H), 3.93 4H), 3.39 2H), 2.44 1H), 2.23 1H), 2.00-1.30 9H), 1.25 J=7H, 3H).
Ethyl (2-Oxo-3-(3-oxobutyl)pyrrolidin-1-yl)acetate A solution of 2-4 (1.1 g, 3.9 mmol), p-TSA (5 mg) and acetone (50 mL) was heated at reflux for 1 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentration to afford 2-5 as a yellow oil.
TLC Rf 0.48 (silica, EtOAc) 1 H NMR (300 MHz, CDC13) 8 4.18 J=7Hz, 2H), 4.01 2H), 3.40 2H), 2.67 J=7Hz, 2H), 2.48 1H), 2.30-1.60 4H), 2.15 (s, 3H), 1.25 J=7Hz, 3H).
Ethyl 1,8]naphthyridin-2-yl)ethyl)pyrrolidin-1 -yl)-acetate (2-6) A mixture of 2-5 (0.77 g, 3.0 mmol), 1-4 (0.55 g, mmol, for preparation see Het, 1993, 36, 2513), L-proline (0.17 g, mmol) and ethanol (25 mL) was heated at reflux for 20 hr. The cooled reaction mixture was concentrated and the residue purified by flash chromatography (silica, EtOAc 5% CH30H/EtOAc) to give 2-6 as a yellow oil.
TLC Rf 0.13 (silica, 10% 1 H NMR (300 MHz, CDC13) 8 9.08 1H), 8.17 1H), 8.12 (d, J=8Hz, 1H), 7.49 J=8Hz, IH), 7.46 1H), 4.15 J=7Hz, 2H), 4.04 2H), 3.42 2H), 3.21 J=8Hz, 2H), 2.60-1.80 1.25 J=7Hz, 3H).
Ethyl (2-Oxo-3-(2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2yl)ethyl)pyrrolidin-1 -yl)acetate (2-7) A mixture of 2-6 (0.87 g, 2.6 mmol), 10% Pd/C (0.5 g), and CH30H (25 mL) was stirred under a hydrogen atmosphere (1 atm) for 2 hr. The catalyst was then removed by filtration through a celite WO 98/08840 PTU9/41 PCTfUS97/14912 94 pad followed by concentration of the filtrate. Flash chromatogrphy (silica, EtOAc 5% CH3OH/EtOAc) gave 2-7 as a yellow oil.
TLC Rf 0. 18 (silica, 5 CH3OH/EtOAc) I H NMR (300 MHz, CDCl3) 857.05 J=7Hz, I1H), 6.40 J=7Hz, 1H), 4.83 (bs, 1H), 4.17 J=7H1z, 2H), 4.03 (in, 2H), 3.40 (in, 4H), 2.80-1.60 (in, I11H), 1.27 J=7Hz, 3H).
(2-Oxo-3 ,6,7 ,8-tetrahydro[ 1 -naphthyridin-2-yl)ethyl)pyrrolidin- I -yl~acetic acid hydrochloride (2-8) A stirred mixture of 2-7 (0.45 g, 1.4 mmol) and 6N HCl ml-) was heated at 501C for 1 h, followed by concentration to give 2-8 as a yellow oil.
I
1 H NMR (300 MHz, CD3 OD) 8 7.60 J=7Hz, I1H), 6.66 J=7Hz, 1H), 4.05 2H), 3.50 (in, 4H), 2.83 (in, 4H), 2.54 (in, 1H), 2.32 (in, 1H), 2.10 (in, 1H), 2.00-1.75 (in, 4H).
(2-Oxo-3 (5,6,7 ,8-tetrahydro [1 -naphthyridin-2-yl)ethyl)pyrro- 11dmn- 1 -yl)acetyl-3(S)-ethynyl-o-alanine ethyl ester (2-11) To a stirred solution of 2-8 (50 mg, 0.15 inmol), 2-9 (29 mg, 0. 17 inmol) (Zablocki et al., J. Med Chem., 1995, 38, 2378), NMM (83 p.L, 0.75 inmol), and CH3CN (1 inL) was added BOP (74 mg, 0.17 mmol). After 20 h, the reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, H20 and brine, dried (MgSO4), and concentrated to give 2-11 as a yellow oil.
TLC Rf 0.24 (silica, 10% CH3OI-IEtOAc).
(2-Oxo-3 (5,6,7,8 -tetrahydro[ 1,81 -naphthy ridin-2-yl)ethyl)pyrrolidin-1I-yl)acetyl-3 (S)-p2yridin-3-yl-o-alanine ethyl ester (2-12) To a stirred solution of 2_-8 (50 mg, 0. 15 minol), 2-10 (44 ing, 0. 17 inmol) (Rico et al., J. Org. Chem., 1993, 58, 7948), NMM (8 3 [tL, 0.75 inmol), and CH3CN (1 mL) was added BOP (74 ing, 0. 17 inmol). After 20 h, the reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, H20 and brine, dried (MgSO4), and concentrated to give 2-12 as a brown oil.
WO 98/08840 PCT/US97/14912 95 TLC Rf 0.24 (silica, 20% CH3OH/EtOAc).
(2-Oxo-3-(2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2yl)ethyl)p2yrrolidin- 1-yI)acetyl-3(S )-ethynvl -5-alanine (2-13) A mixture of 2-1 1 (0.1 g, 0.15 mmol), IN NaOH (300 .tL, and ethanol (1 mL) was stirred at ambient temperature for 1 hr.
Concentration and then flash chromagraphy (silica, 25:10:1:1 15:10:1:1 EtOAcIEtOHINH4OH/IH2O) gave 2-13 as a white solid.
TLC Rf 0. 18 (silica, 10: 10: 1: 1 EtOAc/EtOHINHi4OHIH2O) 1 H NMR (300 MHz, CD3OD) 8 7.45 (in, 11H), 6.50 (mn, 1H), 4.53 (in, 1H), 3.80-3.30 (mn, 5H), 3.05 (mn, 1H), 2.80-2.15 (in, 9H), 2.00-1.75 (in, 4H).
(2-Oxo-3-(2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyl)pyfrolidin-l -yl)acetyl-3 (S)-pvri din -3 -yvI-0-alanine (2-14) A mixture of 2-12 (0.1 g, 0.15 mmtol), IN NaGH (300 RL) and ethanol (1 ml-) was stirred at ambient temperature for 1 hr.
Concentration and the flash chromatography (silica, 25:10:1:1 10: 1:1 EtOAcIEtOH/NH-40H/H20) gave 2-14 as a white solid.
TLC Rf 0. 10 (silica, 10: 10: 1: 1 EtOAcIEtOH/NH4OH/H20)
I
1 H NMR (300 MHz, CD3OD) 8 8.57 (mn, 1H), 8.40 (mn, 1H), 7.86 (in, 1H), 7.40 (mn, 2H), 6.50 (mn, 5.28 (in, 1H), 4.65-4.40 (in, 1H), 3.90-1.80 19H).
WO 98/08840 PCT/US97/14912 -96- SCHEME3 0 0
OH
3 -O~t 3-1 pivaloyl chloride 3-2 0 LN 0 Ph 1) CH 2 PPh 3
OH
2 0
OH-
3 A OH 3-2 2) NaOH
OH
2 0 0 NaN(SiMe 3 2
OH
3 A, N 0 te 3-3 7' F 3 C SO 3 Ph3- Ph 1) NaN 3
OH
2 0
OH-
3 j l- NH 2) PPh 3
H
2 0 NaN(SiMe 3 2 then OH 2 0 3-6 OHCF 3 N >(OEt I 0 rOEt 3-70 Br CH3 0S0 4 Cr \-J then Na1O 4 N NH 2 1-4 praline
OH
3 3-8 WO 98/08840 WO 9808840PCT1US97/14912 -97- SCHEME 3 (cont'd) OEt 0
*HCI
3-11 EDO, HOBT
NMM
,OEt 3-13 WO 98/08840 PCTfUS97/14912 98 SCHEME 3 (cont'd) EDC, HOBT
NMM
H
2 N OEt
S
N *2HCI 2-10 3-14 I NaOH 3-15 4-(Propyl-2-ene)butvric acid (3-2) To a stirred suspension of of methyltriphenylphosphonium bromide (67.7 g, 190 mmol) in 1 L THF at 0° C was added a solution of sodium bis(trimethylsilyl)amide (190 mL, 190 mmol, 1M THF) After an additional 30 minutes, 3-1 ethyl 4-acetylbutyrate (Aldrich Chemical Co.)(25.0 g, 158 mmol) was added, and the mixture stirred for 18 h.
The mixture was filtered, and the filtrate concentrated. The residue was triturated with hexanes, and then filtered. Following evaporative WO 98/08840 PCTIUS97/14912 -99removal of the solvent, the residue was chromatographed on silica gel, eluting with 10% ethyl acetate/hexanes to give the olefin as a colorless oil. TLC Rf 0.52 (10% ethyl acetate/hexanes).
1 H NMR (300 MHz, CHC13) 8 4.71 2H, J=13 Hz), 4.13 2H, J=7 Hz), 2.29 2H, J=7 Hz), 2.05 2H, J= 8 Hz), 1.77 2H), 1.72 (s, 3H), 1.26 3H, J=7Hz).
A solution of the above olefin (15.4 g, 98.6 mmol), 1 N NaOH (150 mL), and EtOH (300 mL) was stirred at ambient temperature for 2 h. Following acidification with 1 N HC1, the mixture was extracted with ether. The ether layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-2 as a colorless oil.
1 H NMR (300 MHz, CHC13) 8 4.70 2H, J=13 Hz), 2.27 2H, J=7 Hz), 2.06 2H, J= 7 Hz), 1.72 (4-(Propyl-2-ene)butanovl)-4(R)-benzyl-2-oxazolidinone (3-3) To a solution of 3-2 (6.0 g, 46.8 mmol) in THF (200 ml) at -78° C was added triethylamine (7.19 mL 51.5 mmol) followed by pivaloyl chloride (6.35 mL 51.5 mmol). The mixture was warmed to 0°C for 1 h, then recooled to -780 C. In a separate flask, of benzyl-2-oxazolidinone (9.15 g, 51.5 mmol) was dissolved in THF (100 mL), cooled to -780 C, and n-BuLi (32.3 mL, 51.5 mmol; 1.6 M hexanes) was added dropwise. After 10 minutes, the lithium oxazolidinone was added to the pivalic anhydride. After 10 minutes, the mixture was warmed to 0° C for 1.5 h. The mixture was then poured into ethyl acetate, washed with aqueous sodium bicarbonate, and dried over magnesium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, dichloromethane) to give 3-3 as a slightly yellow oil.
TLC Rf 0.8 (CH2C12).
1H NMR (300 MHz, CHC13) 5 7.40-7.18 5H), 4.80-4.60 3H), 4.18 2H), 3.30 (dd, 1H, J=3.2, 13.2 Hz), 2.95 2H), 2.76 (dd, 1H, J=9.5, 13.1 Hz), 2.11 2H, J=7.5 Hz), 1.87 2H), 1.74 3H).
WO 98/08840 PCTIS97/14912 -100- 2-Chloroethyltriflate (3-4) To a solution of 1.67 mL (24.8 mmol) of 2-chloroethanol and 3.47 mL (29.8 mmol) of 2,6-lutidine in 20 mL of dichloromethane at 0° C was added 4.59 mL (27.3 mmol) of triflic anhydride. After 1 h, the mixture was diluted with hexanes, washed with ice-cold IN HC1, and dried over sodium sulfate. The solvents were evaporated to give 3-4 as a pink oil.
1H NMR (300 MHz, CHC13) 84.69 2H, J=5.3 Hz), 3.78 2H, J=5.6 Hz).
2(S)-Chloroethyl-4-(propyl-2-ene)butanoyl-(4(R)-benzyl-2oxazolidinone) To a solution of 3-3 (11.0 g, 38.3 mmol) in THF (60 mL) at -780 C was added a solution of sodium bis(trimethylsilyl)amide (42.1 mL, 42.1 mmol; 1M/THF). After 20 min, 3-4 (16.2 ml, 115 mmol) was added over 5 min, and the resulting mixture stirred for 1.5 h at -78° C, then 2 h at -150 C. The mixture was diluted with hexanes, washed with sat.
ammonium chloride, and dried over sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 14% ethyl acetate/hexanes) to give 3-5 as a colorless oil. TLC Rf 0.5 (20% ethyl acetate/hexanes).
IH NMR (300 MHz, CHC13) 8 7.30-7.18 5H), 4.67 3H), 4.19 2H), 3.99 1H), 3.58 2H), 3.33 (dd, 1H, J=3.2, 12.0 Hz), 2.75 (dd, 1H, J=9.7, 13.5 Hz), 2.23 1H), 2.18-1.82 4H), 1.77- 1.60 1H), 1.71 3H).
Ethyl 2-oxo-3(S)-(3-methylenebutyl)pyrrolidine (3-6) A mixture of 3-5 (8.15 g, 23.3 mmol) and NaN3 (4.54 g, 69.8 mmol) in DMSO (120 mL) was heated at 750 C for 2 h. After cooling, the mixture was diluted with ether and hexanes, washed with water, and dried over sodium sulfate. Evaporative removal of the solvent gave the azide as a colorless oil.
TLC Rf 0.5 (20% ethyl acetate/hexanes).
WO 98/08840 PCTIUS97/14912 101 1H NMR (300 MHz, CHC13) 8 7.30-7.22 5H), 4.69 3H), 4.17 2H, J=5.1 Hz), 3.89 1H), 3.38 3H), 2.74 IH), 2.13-1.63 6H), 1.71 3H).
To a solution of of this azide (8.0 g 22.4 mmol) in THF (250 mL) and water (40 mL) was added triphenylphosphine (8.24 g 31.4 mmol) in 4 portions over 5 minutes. This mixture was heated at reflux for 2 h, cooled, and evaporated. The residue was chromatographed (silica gel, 10% chloroform/ethyl acetate) to give 3-6 as a colorless oil.
TLC Rf 0.40 (20% chloroform/ethyl acetate).
1 H NMR (300 MHz, CHC13) 6 6.47 (br s, 1H), 4.73 2H), 3.31 (m, 2H), 2.33 2H), 2.08 3H), 1.81 1H), 1.74 3H), 1.44 (s, 1H).
Ethyl 2-oxo-3(S)-(3-methylenebutyl)pyrrolidin- -yl)acetate (3-7) To a solution of 3-6 (2.50 g, 16.3 mmol) in THF (40 mL) at -78° C was added sodium bis(trimethylsilyl)amide (17.1 mL, 17.1 mmol; 1 M/ THF) dropwise. After an additional 20 min, ethyl bromoacetate (2.17 mL, 19.6 mmol) was added dropwise over 3 min.
After an additional 20 min, 20 mL sat. aqueous NH4C was added, and the cooling bath removed. The layers were separated, the aqueous layer washed with ether, and the combined organic extracts were dried over sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40% ethyl acetate/hexanes) to give 3-7 as a colorless oil.
TLC Rf 0.85 (50% chloroform/ethyl acetate).
1 H NMR (300 MHz, CHC13) 5 4.73 2H), 4.18 2H, J=7.1Hz), 4.06 (dd, 2H, J=17.6, 20.8 Hz), 3.42 2H), 2.44 1H), 2.27 (m, 1H), 2.12 3H), 1.75 1H), 1.74 3H), 1.50 1H), 1.28 (t, 3H, J=7.3 Hz).
Ethyl 2-oxo-3(S)-(3-oxo-butyl)pyrrolidin-l-yl)acetate (3-8) To a solution of 3-7 (3.35 g,14.0 mmol) and Nmethylmorpholine-N-oxide (3.27 g, 28.0 mmol) in THF (10 mL) and WO 98/08840 PCTfUS97/14912 -102water (1 mL) was added Os04 (5.7 mL, 0.56 mmol; 2.5 t-butanol).
After 1 h, NalO4 (5.99 g 28 mmol) in warm water (30 mL) was added over 2 min, and the resulting mixture stirred for 1 h. Water was then added, and the aqueous layer washed with ether and ethyl acetate, and the combined organic extracts were dried over sodium sulfate.
Evaporative removal of the solvent gave 3-8 as a dark oil containing residual Os04.
TLC Rf 0.78 (70:20:10 chloroform/ethyl acetate/MeOH).
1H NMR (300 MHz, CHC13) 8 4.19 2H, J=7.2 Hz), 4.03 2H), 3.41 2H), 2.68 2H, J=9.4 Hz) 2.45 1H), 2.27 1H), 2.17 3H), 1.97 1H), 1.78 2H), 1.28 3H, J=7.2 Hz).
Ethyl 1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1vl)acetate (3-9) A mixture of 3-8 (3.25 g, 13.5 mmol), 1-4, 2-amino-3formylpyridine (2.2 g, 18.2 mmol; for preparation see Synth. Commun.
1987, 17, 1695) and proline (0.62 g, 5.39 mmol) in absolute ethanol mL) was heated at reflux for 15 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH to give 3-9 as a colorless oil.
TLC Rf 0.24 (70:25:5 chloroform/ethyl acetate/MeOH).
1H NMR (300 MHz, CHC13) 8 9.08 1H), 8.16 2H), 7.47 (m, 2H), 4.17 4H), 3.42 2H), 3.21 2H, J=6.0 Hz), 2.56 1H), 2.39 2H), 2.08 1H), 1.87 1H), 1.27 3H, J=7.1 Hz).
Ethyl 2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2yl)ethvllpyrrolidin-1-yl)acetate (3-10) A mixture of 3-9 (3.33 g, 10.2 mmol) and 10% Pd/carbon g) in EtOH (50 mL) was stirred under a balloon of hydrogen for 13 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH to give 3-10 as a colorless oil.
TLC Rf 0.20 (70:20:10 chloroform/ethyl acetate/MeOH).
WO 98/08840 PTU9/41 PCTIUS97/14912 -103- IH NMR (300 MHz, CHC13) 867.05 1H, J=7.3 Hz), 6.38 1H, J=7.3 Hz), 4.88 (br s, 1H), 4.17 (dd, 211I, J=7.0, 14.4 Hz), 4.04 (dd, 2H, J= 17.6, 27.3 Hz), 3.40 (in, 4H1), 2.69 (in, 4H), 2.51 (in, I1H), 2.28 (in, 2H), 1.90 (in, 2H), 1.78 (in, 2H), 1.27 3H, J=6.9 Hz).
2-Oxo-3 ,6,7 ,8-tetrahydro [1 ,8]-naphthyridin-2yl)ethvllpvrrolidin-1I-vl)acetic acid (3 -11) A mixture of 3-10 (0.60 g, 1.81 rmol) and 6N HC1 mL) was heated at 60' C for 1 h. Evaporative removal of the solvent gave 3-1 1 as a yellow oil.
I
1 H NMR (300 MHz, DMSO-d6) 868.4 (br s, I 7.60 I1H, J=7.3 Hz), 6.63 I1H, J=7.3 Hz), 3.92 (dd, 2H, J=17.6, 25.9 Hz), 3.43 (in, 2H), 3.35 (in, 2H), 2.74 (in, 4H), 2.28 (in, 2H), 2.03 (in, 1H), 1.82 (in, 2H), 1.67 (in, 2H).
2-Oxo-3(S)- ,6,7 ,8-tetrahydro [1 ,8]-naphthyridin-2yI~ethyl Ipyrro li din- I yl)acety1- 3 (8)-alkynyl -0-alanine ethyl ester (3-12) A mixture of 3-11 (0.20 g, 0.588 minol), 2-9 (0.157 g, 0.882 minol), EDC (0.147 g, 0.765 inmol), HOBT (0.095 g, 0.706 mmol) and NMM (0.453 inL, 4.12 minol) in CH3CN (3 iL) and DMF (2 inL) was stirred for 20 h. The mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate.
Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroformn/ethyl acetate/MeOH to give 3-12 as a colorless foam.
TLC Rf 0.44 (70:20:10 chloroform/ethyl acetate/MeOH).
I H NMR (300 MHz, CHCl3) 6 7.06 I1H, J=7.3 Hz), 6.3 9 I1H, J=7.3 Hz), 5.07 (mn, I1H), 4.94 (br s, I1H), 4.18 2H, 1=6.1 Hz), 3.95 2H, J=16.1 Hz), 3.39 (mn, 4H), 2.90 1H), 2.68 (in, 6H), 2.50 (in, 1H), 2.27 (mn, 3H), 1.82 (in, 4H), 1.27 3H, 1=7.1 Hz).
2-Oxo-3 ,8-tetrahydro [1 ,8]-naphthyridin-2-yl)ethyl] pyrrolidin-l1-yl)acetyl-3 (S)-alkynyl- 3-alanine (3-13) WO 98/08840PC(S7142 PCTIVS97/14912 -104- To a solution of 312~ (0.050 g, 0. 117 imnol) in EtOH (1 mL) was added IN NaOH (0.164 ml, 0.164 mmol). After stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 3-13 as a colorless foam.
TLC Rf 0.26 (25: 10: 1:1 ethyl acetatelEtOH/water/NH4OH).
1 H NMR (300 MHz, DMSO-d6) 857.75 (br s, 1H), 7.14 111, J=7.3 Hz), 6.31 IH, J=7.3 Hz), 4.74 (in, 11H), 3.90 1H, J=16.6 Hz), 3.67 1H, J=16.6 Hz), 3.23 (in, 4H), 2.57 (in, 7H), 2.30 (in, 1H), 2.11 (in, 2H), 1.73 (mn, 2H), 1.59 (mn, 2H).
2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro -naphthyridin-2-yl)ethyl] p1yrrolidin-l1-vl)acetvl-3(S)-pvyridin-3 -yl-D-alanine ethyl ester (3-14) A mixture of 3-11 (0.30 g, 0.882 mmol), 2-10 (0.354 g, 1.3 2 inmol) EDC (0.220 g 15 mmol), HOBT 143 g, 1.05 inmol) and NMM (0.680 mL (6.18 iniol) in CH3CN (5 mL) and DMF (3 mL) at 0' C was stirred for 10 min, then allowed to warm and stir for 20 h.
The mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20: chloroform/ethyl acetate/MeOH to give 3-14 as a colorless foam.
TLC Rf 0.31 (70:20:10 chloroform/ethyl acetate/MeOH).
1 H NMR (300 MHz, CHCl3) 5 8.55 1H, J=2.2 Hz), 8.50 (dd, 1H, J= 4.6 Hz), 7.64 (mn, 2H), 7.23 (in, 1 7.05 1 H, J=7.3 Hz), 6.3 8 1H, J=7.3 Hz), 5.40 (mn, 1H), 4.98 (br s, 1H), 4.01 (mn, 4H), 3.39 (in, 4H), 2.85 (in, 2H), 2.68 (in, 41-1), 2.49 (in, 1H), 2.25 (mn, 2H), 1.83 (in, 4H), 1.16 3H, J=7.2 Hz).
2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro -naphthyridmn-2yl)ethvllpyrrolidin-1I-vl)acetyl-3 (S)-pvridin-3 -yl-5-alanine (3-15) To a solution of 3 -1J4 (0.049 g, 0. 102 inmol) in THF (1 mL) and water (0.3 mL) at 0' C was added I M LiOH 112 ml, 0. 112 inmol). After warming to ambient temperature and stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica WO 98/08840 PTU9141 PCT/US97/14912 -105gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 3-15 as a colorless foamn.
TLC Rf 0. 15 (25: 10: 1:1 ethyl acetate/EtOH/waterfNH4OH).
I H NMR (300 MHz, DMSO-d6) 8 8.74 I1H, J=8.3 Hz), 8.51 (in, 1H), 8.42 (mn, 2H), 7.70 1H, J=8.1 Hz), 7.33 (in, 1H), 7.21 1H, J=7.3 Hz), 6.36 1H, J=7.3 Hz), 5.14 (in, 1H), 4.00 1H, J=16.8 Hz), 3.70 1H, J=16.6 Hz), 3.30 (in, 4H), 2.68 (in, 7H), 2.20 (mn, 3H), 1.71 (in, 4H).
SCHEME 4 N N N~>OH H0 *HCI0 4-1 EDC, HOBT
NMM
H
2 N OEt *HCI 0 2-9
H
OEt
NN'-
H I 0 0 4-2 I NaOH WO 98/08840 PTU9/41 PCTIUS97/14912 106- SCHEME 4 (cont'd)
OH
0 H HCI EDC, HOBT
NMM
2-10 .OEt I NaOH 2-Oxo-3 ,6,7,8-tetrahydro -naphthyridin-2yl)ethyllpyrrolidin- I -yl)acetyl-3 (S )-alkynyl-D-alanine ethyl ester (4-2) Prepared from 4-1 (prepared by the method used to prepare 3-11, utilizing (S)-(-)-4-benzyl-2-oxazolidmnone) and 29 by the method used to prepare 3-12.
WO 98/08840 PTU9/41 PCTIUS97/14912 -107- IH NMR (300 MHz, CHC13) 8 7.06 Ill, J=7 Hz), 6.39 1H), J=7 Hz), 5.06 (in, 1H), 4.84 (br s, 1H), 4.16 2H, J=6 Hz), 3.93 (in, 2H), 3.38 (in, 4H), 2.68 (in, 6H), 2.52 (mn, 1H), 2.25 (in, 2H), 1.90 (in, 2H), 1.78 (in, 2H), 1.26 3H, J=7Hz).
2-Oxo-3(R)- ,6,7 ,8-tetrahydro 8]-naphthyridin-2yl)ethyllpyrrolidin-l1-yI)acetyl-3 (S)-alkynvl -o-alanine (4-3) Prepared from 4-2 (0.05 g, 0. 11 minol) by the method used to prepare 3-13.
IH NMR (300 MHz, CD3OD, 1 drop IN NaOD) 8 7.11 1H, J=7 Hz), 6.40 1H, J=7 Hz), 4.90 (mn, 1H), 3.94 2H, J= 17 Hz), 3.39 (in, 4H), 2.69 2H, J= 6 Hz), 2.60 (in, 2H), 2.52 J=7 Hz), 2.49 (in, 1H), 2.27 (in, 1H), 2.13 (in, 1H), 1.85 (in, 4H), 1.68 (in, 1H).
2-Oxo-3 ,8-tetrahydro[ 1,8]-naphthyridin-2-yl)ethyl] pyrrolidin-l1-vl)acetyl-3(S )-pyridin-3 -v1-p-alanine ethyl ester (4-4) Prepared from 4-1 (0.35 g, 1.0 mrnol) and 2-10 (0.33 g, 1.2 inmol) by the method used to prepare 3-14.
1 H NMR (300 MHz, CHC13) 5 8.55 I1H, J= 2 Hz), 8.55 (dd, ILH, J= 2 ,5 Hz), 7.61 (in, 1H), 7.54 (in, 1H), 7.06 1H), 6.38 1H, J=7 Hz), 5.40 (mn, 1H), 4.90 (br s, 1H), 4.05 2H, J=7 Hz), 3.95 (in, 2H), 3.42 (in, 4H), 2.85 (dd, 2H, J=2, 6 Hz), 2.67 (in, 4H1), 2.53 (in, I1H), 2.27 (mn, 2H), 1.90 (in, 2H), 1.78 (mn, 211), 1.16 (mn, 3H, 1=7 Hz).
2-OXo-3(R)-[2-(5 ,6,7 ,8-tetrahydro-[ 1,8]-naphthyridin-2yl)ethyllpyrrolidin-l1-vl)acetyl-3 (S)-pyridin-3 -yl-o-alanine Prepared from 4-4 (0.16 g, 0.33 mmol) by the method used to prepare 3-15.
IH NMR (300 MHz, CD3OD) 5 8.57 1H), 8.42 (mn, 1H), 7.86 1H, J=6 Hz), 7.43 (in, 2H), 6.51 Ill, J=7 Hz), 5.28 (in, 1H), 4.63 1H, J= 17 Hz), 3.60 (in, 2H), 3.47 I1H, J= 17 Hz), 3.3 5 (mn, 3H), 3.14 (td, 1H, J=5, 13 Hz), 2.75 (in, 5H), 2.42 (in, 1H), 2.23 (in, 1H), 1.90 (in, 4H).
WO 98/08840 PTU9/41 PCTIUS97/14912 -108- 0 H, N H
U)
B00 2 0, DMAP,
CH
3 CN, 0 B0C'..N'KN
BOO
5-2 5-1 0 HN
N
I( I42 4 3 CN, 50 0
C
BOO
LiN(TMS) 2
DMF
cO 5-4
I
5-3 1-2 toluene,
TEA
r 0 LiN(TMS) 2 DMF N'JN"CO 2 Et ethyl iodoacetateU 5-6 WO 98/08840 WO 988840PCT/US97/14912 5-6 109 SCHEME 5 (contXd
D
2 Et pTSA, acetone, ref lux C- N Pd/C, ethanol, 0 0 K N'IN"CO 2 Et 5-7- L-prol ethani ref lux i ne, oI, 1-4 -C0 2 Et 5-8 -C0 2
R
6N HCI R Et, 5-9 R H, 5-10 EDO, HOBT, NMM, DMF, 1-9
H
N
C0 2
R
NN
R Et, 5-11 R H, 5-12 1 N NaOH, ethanol WO 98/08840 PCTIUS97/14912 -110- 1.3-Di-tert-buyloxycarbonyl-tetrahydropyrimidine (5-2) A heterogeneous mixture of 5-1 (10.0 g, 100 mmol), (48 g, 220 mmol), DMAP (20 mg), and CH3CN (500 mL) was heated for 40 hr at 65°C followed by addition of DMF (100 mL) and then continued heating for 24 hr. The cooled reaction mixture was diluted with EtOAc and then washed with H20, sat. NaHCO3, IN HC1, and brine, dried (MgSO4), and concentrated. The residue was triturated with hexanes to give 5-2 as a yellow solid.
TLC RF 0.93 (EtOAc); 1 HNMR (300 MHz, CDC13) 8 3.68 J 7 Hz, 4H), 2.00 2H), 1.48 18 H).
Tert-Butyloxycarbonyl-tetrahydropyrimidine (5-3) A solution of 5-2 (19.0 g, 63 mmol), Mg(C104)2 (2.8 g, 12.7 mmol), and CH3CN was heated at 50 oC for 2 hr. The cooled solution was diluted with CHC13 and then washed with IN HC1, sat.
NaHCO3, and brine, dried (MgS04), and concentrated. Flash chromatography (silica, 75% EtOAc/ hexanes -4EtOAc) gave 5-3 as a brown solid.
TLC RF 0.26 (silica, EtOAc); 1HNMR (300 MHz, CDC13) 8 5.50 (bs, 1H), 3.70 2H), 3.29 (m, 2H), 1.97 2H), 1.48 9H).
Tert-Butyloxycarbonyl-2-oxo-3-(3-ethylene glycolbutyl)tetrahydropyrimidine (5-4) To a stirred solution of 5-3 (3.2g, 16.1 mmol) and DMF mL) was added LiN(TMS)2 (21 mL, 1M/hexanes). After minutes, the iodide 1-2 (8.6 g, 35.2 mmol) in DMF (10 mL) was added and the reaction mixture heated at 50 °C for 2 hours. The cooled solution was diluted with CHC13 and then washed with H20 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, to 75% EtOAc/hexanes) gave 5-4 as an orange oil.
TLC RF 0.74 (silica, 70:15:15 CHCl3/EtOAc/CH30H); WO 98/08840 PCT/US97/14912 -111 H NMR (300 MHz, CDC13) 8 3.93 4H), 3.66 J= 6Hz, 2H), 3.,44 2H), 3.30 2H), 1.96 2H), 1.48 9H), 1.32 3H).
1-Oxo-2-(3-ethylene glycol-butyl) tetrahydro-pyrimidine A mixture of 5-4 (3.0 g, 9.5 mmol), TFA (1.5 mL, and toluene (30 mL) was stirred at ambient temperature for 20 minutes, concentrated and the residue azeotroped with toluene to remove excess TFA. The residue was then dissolved in toluene (30 mL) and treated with NaHCO3 filtered, and the filtrate concentrated to give a yellow oil. Flash chromatography (silica, 70:15:15 CHCl3/EtOAc/ gave 5-5 as a yellow oil.
TLC RF 0.63 (silica, 70:15:15 CHC13/EtOAc/CH30H); 1H NMR (300 MHz, CDC13) 8 5.16 (bs, 1H), 3.94 4H), 3.40 (m, 2H), 3.24 4H), 1.90 2H), 1.34 3H).
Ethyl 2-oxo-3-[3-ethylene glycol-butyl]tetrahydropyrimidin-l-ylacetate (5-6) To a stirred solution of 5-5 (2.0 g, 9.3 mmol) and DMF mL) was added LiN(TMS)2 (12.1 mL, 1.0 M/THF). After 20 min, ethyl iodoacetate (1.66 mL, 14.0 mmol) was added followed by heating at 60 0 C for 1 hr. The cooled solution was diluted with EtOAc and then washed with H20, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 50% to EtOAc/hexanes) gave 5-6 as a colorless oil.
TLC RF 0.72 (silica, 70:15:15 CHCl3/EtOAc/CH30H); 1H NMR (300 MHz, CDC13) 8 4.18 J=7Hz, 2H), 3.93 4H), 3.42 2H), 3.34 4H), 1.98 2H), 1.92 2H), 1.34 3H), 1.25 J=7Hz, 3H).
Ethyl 2-oxo-3-[3-oxo-butylltetrahydro-pyrimidin- -yl-acetate (5-7) A solution of 5-6 (750 mg, 2.5 mmol), p-TSA (10 mg), and acetone (30 mL) was refluxed for 1 hr. The cooled solution was diluted with CHC13 and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 5-7 as a yellow oil.
WO 98/08840 PCT[US97/14912 -112- TLC RF 0.36 (silica, 10% 1 H NMR (300 MHz, CDC13) 8 4.17 J=7Hz, 2H), 3.56 2H), 3.34 4H), 2.76 J=7Hz, 2H), 2.17 3H), 2.00 2H), 1.27 J=7Hz, 3H).
Ethyl 2-oxo-3-[2-naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-l-ylacetate (5-8) A mixture of 5-7 (600 mg, 2.3 mmol), 1-4 (343 mg, 2.8 mmol), L-proline (175 mg), and ethanol (25 mL) was heated at reflux for 18 hr. The cooled reaction mixture was concentrated and the residue purified by flash chromatography (silica, 10% gave 5-8 as a yellow solid.
TLC RF 0.21 (silica, 10% H NMR (300 MHz, CDC13) 8 9.10 1H), 8.19 1H), 8.14 (d, J=8Hz, 1H), 7.52 J=8Hz, 1H), 7.44 1H), 4.18 J=7Hz, 2H), 3.83 2H), 3.32 6H), 1.93 2H), 1.24 J=7Hz, 3H).
Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro-[ 1,8]-naphthyridine-2-yl)ethyl] tetrahydropyrimidine-1 -yl-acetate (5-9) A mixture of 5-8 (600 mg, 1.75 mmol), 10% Pd/C (300 mg), and ethanol (10 mL) was stirred at ambient temperature under a hydrogen atmosphere (1 atm) for 20 hr. The catalyst was removed by filtration through a celite pad and the filtrate concentrated to give 5-9 as a yellow oil.
1H NMR (300 MHz, CDC13) 8 7.04 J=8Hz, 1H), 6.42 J=8Hz, 1H), 4.80 (bs, 1H), 4.22-4.03 4H), 3.60 2H), 2.78 2H), 2.66 2H), 1.96 4H), 1.24 J=7Hz, 3H).
2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthridin-2-yl)tetrahydropyrimidin-l-vl-acetic acid (5-10) A solution of 5-9 (600 mg, 1.73 mmol) and 6N HCI mL) was heated at 50 0 C for 2 hr. The solution was concentrated followed by azeotropic removal of H20 with CH3CN to give 5-10 as a yellow solid.
WO 98/08840 WO 9808840PCTIUS97/14912 113 1HNMR (300 MHz, CD3OD) 5 7.58 J=8Hz, 1H), 6.63 J=8Hz, 1H), 3.98 2H), 3.62 J=7Hz, 2H), 3.50 (in, 2H), 3.36 (in, 4H), 2.93 (in, 2H), 2.80 (in, 2H), 2.00 (mn, 41-).
Ethyl 2-oxo-3- ,6 ,7,8-tetrahydro- naphthyridin-2-yl)ethyl] tetrahydropyrimidin-l-yl-acetyl-3 (S)-p2yridin-3 -yI-3-alanine (5-11) To a stirred solution of 5-10. (250 mg, 0.70 minol), 1-9 (210 mng, 0.77 mmol), EDC (148 ing, 0.77 minol), HOBT (95 mg, 0.70 mmol), CH3CN (2 mL), and DMF (2 mL) was added NMM (542 pL, 4.9 inmol). After stirring at ambient temperature for 20 hr, the reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 70:15:15 CHCl3IEtOAc/CH3OH) gave 5-1-1 as a colorless oil.
TLC RF 0.31 (silica, 70:15:15 CHC13I EtOAc/CH3OH); I H NMR (300 MHz, CDCI3) 6 8.58 (in, 1H), 8.50 (in, 1H), 7.94 (in, 1H), 7.66 (in, 1H), 7.22 (in, 1H), 7.05 J=8Hz, lH), 6.40 J=8Hz, 1H), 5.43 (in, lH), 4.06 J=7Hz, 2H), 4.02 (in, 1H), 3.90 (in, lH), 3.60 (in, 2H), 3.39 (mn, 2H), 3.29 (in, 2H), 3.19 (mn, 2H), 2.88 (in, 2H), 2.77 (in, 2H), 2.70 (in, 2H), 1.90 (mn, 4H1), 1.16 J=7Hz, 3H).
2-Oxo-3- ,6,7 ,8-tetrahydro-[ [1,8]naphthyridin-2-yl I ethyl] tetrahydropyrimidin- 1-yl-acetyl-3 )-pyridin- 3 -yi- -alanine (5-12) A mixture of 5-11 (100 mg, 0.22 inmol), IN NaOH (300 PiL), and ethanol (1 mL) was stiffed at amnbient temperature for 1 hr, followed by concentration. Flash chromatography (silica, 25: 10: 1:1 to 10: 1:1 EtOAc/EtOHIH4OHIH2O) gave 5 -12 as a white solid.
TLC RF 0.22 (silica, 10: 10: 1: 1 EtOAc/ethanol/NI-40H, IHNMR (300 MHz, CD3OD) 6 8.66 (in, 1H), 8.39 (mn, 1H), 7.95 (in, 1 7.53 J=8Hz, IlH), 7.40 (mn, I1H), 6.66 1=8Hz, 1 5.18 (in, 1H), 4.27 J=7Hz, 1H), 4.16 (in, 1H), 3.64 J=7Hz, lH), 3.50-3.10 (in, 8H), 3.00-2.65 (in, 6H), 1.95 (mn, 4H).
WO 98/08840 PCTIUS97/14912 -114- 0 H, N )N'N H 6-1 0 BOCN'-K' BOC
BOC
2 O, DMAP N N
CH
3 CN, 65 0 C1 6-2 4 2
,ICH
3 CN, 5000 BOC LiN(TMS) 2
DMF
0 H, N' BOO 6-3 6-4 1-2 toluene,
TEA
CO
2 Et H LiN(TMS),, DMF, ethyl lodloacetate 6-6 PCTIUS97/14912 WO 98/08840 115 SCHEME 6 (contMd 0 0 -C2tpTSA, -l-N-jNC 2 Et CEtacetone,-I reflux 6-7 6-6 L-proline, ethanol, 1-4 ref lux N'COEt Pd/C, ethanol, H 2 6-8 R Et, 6-9 6
C
R H, 6-10 EDC, HOBT, NMM, DMF, 1-9 2
R
1 N NaOH, ethanol R Et, 6-1 1 R H, 6-12D WO 98/08840 PCTIUS97/14912 -116- 1,3-Di-tert-buyloxycarbonyl-imidazolidin-2-one (6-2) A heterogeneous mixture of 6-1 (10.0 g, 116 mmol), (56 g, 255 mmol), DMAP (20 mg), and CH3CN (400 mL) was heated for 18 hr at 60 0 C. The cooled reaction mixture was diluted with EtOAc and then washed with H20, sat. NaHCO3, IN HC1, and brine, dried (MgSO4), and concentrated. The residue was triturated with hexanes to give 6-2 as a white solid.
TLC RF 0.91 (EtOAc); IH NMR (300 MHz, CDC13) 8 3.73 4H), 1.53 18 H).
Tert-Butyloxycarbonyl-imidazolidin-2-one (6-3) A solution of 6-2 (28.0 g, 98 mmol), Mg(C104)2 (4.3 g, mmol), and CH3CN (400 mL) was heated at 50 OC for 3 hr. The cooled solution was diluted with CHC13 and then washed with IN HC1, sat.
naHCO3, and brine, dried (Mg S04), and concentrated. Flash chromatography (silica, 50% EtOAc/ hexanes -*EtOAc) gave 6-3 as a yellow solid.
TLC RF 0.31 (silica, EtOAc); 1H NMR (300 MHz, CDC13) 8 6.27 (bs, 1H), 3.86 2H), 3.47 (m, 2H), 1.50 9H).
1-Tert-Butyloxycarbonyl-3-(3-ethylene glycol-butyl)imidazolidin-2-one (6-4) To a stirred solution of 6-3 (4.5 g, 24 mmol) and DMF mL) was added LiN(TMS)2 (26.6 mL, IM/hexanes). After 20 minutes, the iodide 1-2 (8.6 g, 35.2 mmol) in DMF (10 mL) was added and the reaction mixture heated at 60 oC for 4 hours. The cooled solution was diluted with CHC13 and then washed with H20 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 30 EtOAc/hexanes) gave 6-4 as an yellow solid.
TLC RF 0.71 (silica, 70:15:15 CHCl3/EtOAc/CH30H); IH NMR (300 MHz, CDC13) 5 3.93 4H), 3.75 2H), 3.36 4H), 1.90 2H), 1.53 9H), 1.34 3H).
WO 98/08840 PCT/US97/14912 -117- 1-(3-Ethylene glvcol-butvl)imidazolidin-2-one A mixture of 6-4 (4.0 g, 13.3 mmol), TFA (3 mL, and toluene (60 mL) was stirred at 50 0 C for 60 minutes, concentrated and the residue azeotroped with toluene to remove excess TFA. The residue was then dissolved in toluene (30 mL) and treated with NaHCO3 (3g), filtered, and the filtrate concentrated to give a yellow oil. Flash chromatography (silica, 70:25:5 CHCl3/EtOAc/CH30H) gave 6-5 as a white solid.
TLC RF 0.58 (silica, 70:15:15 CHCI3/EtOAc/CH30H); 1 H NMR (300 MHz, CDC13) 8 4.25 (bs, 1H), 3.94 4H), 3.44 (m, 4H), 3.32 2H), 1.90 2H), 1.35 3H).
Ethyl 2-oxo-3-[3-ethylene glycol-butyllimidazolidin- -yl -acetate (6-6) To a stirred solution of 6-5 (2.0 g, 10 mmol) and DMF mL) was added LiN(TMS)2 (11 mL, 1.0 M/THF). After 20 min, ethyl iodoacetate (3.5 mL, 30 mmol) was added at ambient temperature.
After 3 hr the solution was diluted with EtOAc and then washed with sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 50% to 75% EtOAc/hexanes) gave 6-6 as a colorless oil.
TLC RF 0.71 (silica, 70:15:15 CHCI3/EtOAc/CH30H); 1H NMR (300 MHz, CDC13) 5 4.18 J=7Hz, 2H), 3.93 4H), 3.91 2H), 3.50-3.30 6H), 1.90 2H), 1.92 2H), 1.35 3H), 1.25 J=7Hz, 3H).
Ethyl 2-oxo-3-[3-oxo-butyllimidazolidin- 1 -yl-acetate (6-7) A solution of 6-6 (1.4 g, 4.9 mmol), p-TSA (10 mg), and acetone (30 mL) was refluxed for 1 hr. The cooled solution was diluted with CHC13 and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 6-7 as a yellow oil.
TLC RF 0.34 (silica, EtOAc); 1H NMR (300 MHz, CDC13) 8 4.17 J=7Hz, 2H), 3.94 2H), 3.48 2H), 3.42 4H), 2.72 J=7Hz, 2H), 2.17 3H), 1.27 J=7Hz, 3H).
WO 98/08840 PCT/US97/14912 118- Ethyl 2-oxo-3-[2-naphthyridin-2-vl)ethyllimidazolidin-l-vl-acetate (6-8) A mixture of 6-7 (1.0 g, 4.1 mmol), 1-4 (604 mg, 4.9 mmol), L-proline (238 mg), and ethanol (50 mL) was heated at reflux for 20 hr. The cooled reaction mixture was concentrated and the residue purified by flash chromatography (silica, 70:25:5 CHC13/EtOAc/CH30H) gave 6-8 as a yellow oil.
TLC RF 0.42 (silica, 70:15:15 CHCl3/EtOAc/CH30H); 1H NMR (300 MHz, CDC13) 8 9.10 1H), 8.19 1H), 8.14 (d, J=8Hz, 1H), 7.52 J=8Hz, 1H), 7.44 1H), 4.17 J=7Hz, 2H),, 3.81 2H), 3.42 4H), 3.32 4H), 1.24 J=7Hz, 3H).
Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridine-2yl)ethvllimidazolidin- -yl-acetate (6-9) A mixture of 6-8 (1.1 g, 3.35 mmol), 10% Pd/C (500 mg), and ethanol (30 mL) was stirred at ambient temperature under a hydrogen atmosphere (1 atm) for 20 hr. The catalyst was removed by filtration through a celite pad and the filtrate concentrated to give 6-9 as a colorless oil.
TLC RF 0.11 (silica, 70:25:5 CHCl3/EtOAc/CH30H); H NMR (300 MHz, CDC13) 8 7.04 J=8Hz, 1H), 6.42 J=8Hz, 1H), 4.80 (bs, 1H), 4.22-4.03 4H), 3.96 2H), 3.55 2H), 3.40 2H), 2.78 2H), 2.68 2H), 1.90 2H), 1.24 J=7Hz, 3H).
2-Oxo-3-[2-(5,6,7,8-tetrahydro-[ 1,8]naphthridin-2-yl)imidazolidin-l-ylacetic acid (6-10) A solution of 6-9 (1.0 g, 3.0 mmol) and 6N HCI (40 mL) was heated at 60°C for 1 hr. The solution was concentrated followed by azeotropic removal of H20 with CH3CN to give 6-10 as a yellow solid.
1H NMR (300 MHz, CD30D) 8 7.58 J=8Hz, 1H), 6.63 J=8Hz, 1H), 3.98 2H), 3.50 4H), 3.36 4H), 2.93 2H), 2.82 (m, 2H), 1.97 4H).
WO 98/08840 PTU9I41 PCTIUS97/14912 -119- Ethyl 2-oxo-3- ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2vl)ethvllimidazolidin-l-vl-acetyl-3 (S)-p2yridin-3-yl-D-alanine (6-11) To a stirred solution of 6-10 (240 mg, 0.70 mmol), 1-9 (207 mg, 0.77 mmol), EDC (269 mg, 1.4 mmol), HOBT (95 mg, 0.70 mmol), and CH3CN (3 mL) was added NMM (619 piL, 5.6 mmol).
After stirring at ambient temperature for 20 hr, the reaction mixture -was diluted with EtOAc and then washed with H20, sat. NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 70:15:15 CHCI3/EtOAc/CH3OH) gave 6-1 1 as a colorless oil.
TLC RF 0.41 (silica, 70:15:15 CHC13/ EtOAc/CH3OH); 1 H NMR (300 MHz, CDCl3) 8 8.59 (in, 1H), 8.50 (in, 1H), 7.94 (mn, 1H), 7.66 (in, 1H), 7.22 (in, 1H), 7.05 J=8Hz, 1H), 6.40 J=8Hz, lH), 5.43 (in, 1H), 4.06 J=7Hz, 2H), 3.85 (in, 1H), 3.55 (in, 2H), 3.40 (in, 2H), 3.33 (in, 4H), 2.90 (in, 2H), 2.77 (mn, 2H), 2.70 (in, 2H), 1.90 (in, 2H), 1.77 (in, 2H), 1. 18 J=7Hz, 3H).
2-Oxo-3 ,6,7 ,8-tetrahydro-[ 1,8jjnaphthyridin-2-ylI Jethylimidazolidin- 1-yl-acetyl-3-(S)-pvridin-3-vl- D-alanine (6-12) A mixture of 6-11 (160 mg, 0.33 inmol), IN NaOH (500 jiL), and ethanol (1 inL) was stirred at ambient temperature for 1 hr, followed by concentration. Flash chromatography (silica, 25: 10: 1:1 to 15:10:1:1 EtOAc/EtOH/NH4OH/-20) gave 6-12 as a white solid.
TLC RF 0.21 (silica, 10: 10: 1: 1 EtOAc/ethanol/NH4OH, I11 NMR (300 MHz, CD3OD) 8 8.66 (in, 1H), 8.39 (in, lH), 7.95 (in, 1H), 7.53 J=8Hz, 1H), 7.40 (mn, 1H), 6.66 J=8Hz, 1H), 5.22 (in, 1H), 3.93 J=17 Hz, 1H), 3.74 J=17H1z, 1H), 4.00-3.20 (in, 9H), 3.00-2.65 (in, 6H), 1.89 (mn, 4H).
WO 98/08840 WO 988840PCT[US97/14912 120- SHEME7 0 2 1-
H
N
HCI.H- 2 NN- C02Et 7-1 4-1 EDO, HORT, NMM, CH 3
ON
3 7-2 1N NaOH, ethanol 7-3 WO 98/08840 PTU9141 PCT/(JS97/14912 121 Ethyl 2-oxo-3(R)-[2-(5,6 ,7 ,8-tetrahydro- [1 ,8]naphthyridin-2vb~ethvllpvrirolidin-l-yl)acetyl-3(R)-(2-ethvlindol-3 -v1)-fo-alanine (7-2) To a stirred solution of 4-1. (175 mg, 0.52 mmol), 7-1 (214 mg, 0.72 mmol; for preparation see US 5,321,034), EDC (197 mg, mmol), HOBT (70 mg, 0.52 mmol), and CH3CN (3 mL) was added NMM (498 pL, 4.1 minol). After stirring at ambient temperature for hr, the reaction mixture was diluted with EtOAc and then washed with H20, sat. NaHCO3, brine, dried (MgSO4), and concentrated.
Flash chromatography (silica, 70:25:5 CHCl3IEtOAc/CH3OH) gave 7-2 as a white solid.
TLC RF 0. 11 (silica, 70:25:5 CHC13/ EtOAc/CH3OH); IHNMR (300 MHz, CDCI3) 5 8.29 (bs, IH), 7.55 J 7 Hz, 1H), 7.36 J 7 Hz, 1H), 7.20-7.00 (in, 6.63 J =7 Hz, 1H), 6.39 J 7 Hz, I1H), 4.30 (in, I1H), 4. 10 J=7Hz, 2H), 3.94 J =17 Hz, 1H), 3.83 J 17 Hz, 1H), 3.36 (in, 4H), 2.80 (in, 2H), 2.69 (in, 3H), 2.53 J= 6 Hz, 2H), 2.50 (mn, 1H), 2.24 (in, 2H), 1.93 (in, 4H), 1.75 (in, 2H), 1.18 J=7Hz, 3H).
2-Oxo-3 ,6,7 ,8-tetrahydro-[ 1, 8]naphthyridin-2vlI)ethyllpvrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3 -yl)-fD-alanine (7-3) A mixture of 7-2 (60 mng, 0.11 inmol), IN NaOH (132 pL), and ethanol (1 inL) was stirred at ambient temperature for 1 hr, followed by concentration. Flash chromatography (silica, 25: 10: 1:1 to 15:10:1:1 EtOAc/EtOH/NH4OHII-20) gave 7-3 as a white solid.
TLC RF 0. 12 (silica, 10: 10: 1: 1 EtOAc/ethanolfNH4OHIH2O); H NMR (300 MHz, CD3OD) 8 7.52 J 7 Hz, lH), 7.43 J 7 Hz, lH), 7.30 J 8 Hz, 1H), 7.05 (in, 2H), 6.92 (in, 1H), 6.48 J= 7 Hz, 1H), 4.54 J 17 Hz, 1H), 4.27 (mn, 1H), 3.50-1.70 (in, 22H).
WO 98/08840 PTU9141 PCT/US97/14912 122 SCHEME8 Synthesis of Radioligand for SPA Assay
H
2 N <.CO 2
H
0 H NH 2 8-1 I--&S0 2 01 NaOH, dioxane
H
2 0 0 H N 1. Br 2 NaOH,
H
2 0 2. HCI H2N H SO 2
IHCI
EtOH
HCI.H
2 N -SCO2H23 H N 8-42 .WO 98/08840 PTU9/41 PCTIUS97/14912 123 SCHEME 8 (ContMd \7N
CO
2
CH
2
CH
3
H
2
N
H
2 Pd/C EtOH 6N HOI
HCI.H
2 N -,C02C2CH3 H HNSO 2
C
6
H
4
I
8-4 EDC, HOBT, NMM, DMF
NH
0020 H 2 0H 3 WO 98/08840 PTU9/41 PCT/US97/14912 124- SCHEME 8 (Cont'd)
I
NH
CO
2
CH
2 C H 3 6N HOI 6000
I(CH,
3 Sn) 2 Pd(PPh 3 4 dioxane, 900 C Sn(CH 3 3 H0 2
S
ly -CO 2
H
8-9 1251 8-10 -WO 98/08840 PCT/US97/14912 125 N-(4-Iodo-phenylsulfonylamino)-L-asparagine (8-2) To a stirred solution of acid 8-1 (4.39 g, 33.2 mmol), NaOH (1.49 g, 37.2 mmol), dioxane (30 ml) and H20 (30 ml) at 0 C was added pipsyl chloride (10.34 g, 34.2 mmol). After ~5 minutes, NaOH (1.49, 37.2 mmol) dissolved in 15 ml H20, was added followed by the removal of the cooling bath. After 2.0 h, the reaction mixture was concentrated. The residue was dissolved in H20 (300 ml) and then washed with EtOAc. The aqueous portion was cooled to 0°C and then acidified with concentrated HC1. The solid was collected and then washed with Et20 to provide acid 8-2 as a white solid.
1 H NMR (300 MHz, D20) 8 7.86 2H, J=8Hz), 7.48 2H, J=8Hz) 3.70 1H), 2.39 2H).
2(S)-(4-Iodo-phenylsulfonylamino)--alanine (8-3) To a stirred solution of NaOH (7.14 g, 181.8 mmol) and (40 ml) at 0°C was added Br2 (1.30 ml, 24.9 mmol) dropwise over a ten minute period. After -5 minutes, acid 8-2 (9.9 g, 24.9 mmol), NaOH (2.00 g, 49.8 mmol) and H20 (35 ml) were combined, cooled to 0°C and then added in a single portion to the reaction. After stirring for 20 minutes at 0°C, the reaction was heated to 90 0 C for 30 minutes and then recooled to 0°C. The pH was adjusted to -7 by dropwise addition of concentrated HC1. The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid 8-3 as a white solid.
IH NMR (300 MHz, D20) 8 8.02 2H, J=8Hz), 7.63 2H, J=8Hz), 4.36 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 1H).
Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-p-alanine-hydrochloride (8-4) HCI gas was rapidly bubbled through a suspension of acid 8-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0°C for 10 minutes. The cooling bath was removed and the reaction was heated to 60 0 C. After 18 h, the reaction was concentrated to provide ester 8-4 as a white solid.
1H NMR (300 MHz, CD30D) 8 7.98 2H, J=8Hz), 7.63 2H, J=8Hz), 4.25 1H, J=5Hz), 3.92 2H), 3.33 1H), 3.06 1H), 1.01 3H, J=7Hz).
WO 98/08840 PTU9/41 PCT[US97/14912 -126 Ethyl 4- r2- (2-Aminopyridin-6-vl)ethyl-lbenzoate A mixture of ester 9-5 (700 mg, 2.63 minol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 95/3 27 10, published December 7, 1995) Pd/C (350 mg) and EtOH were stirred under 1 atmn H2. After 20 h, the reaction was filtered through a celite pad and then concentrated to provide ester 9-5 as a brown oil.
TLC Rf 0.23 (silica, 40% EtOAc/hexanes) 1 H NMR (300 MHz, CDCI3) 5 7.95 2H, J=8Hz), 7.26 (in, 3H), 6.43 LH, J=7Hz), 6.35 1H, J=8Hz), 4.37 (in, 4H), 3.05 (in, 2H), 2.91 (in, 2H), 1.39 3H, J=7Hz).
4- [2-(2-Aminopyridin-6-vl)ethvllbenzoic acid hydrochloride (8-6) A suspension of ester 8-5 (625 mng, 2.31 inmol) in 6N HCl (12 ml) was heated to 60'C. After -20 h, the reaction was concentrated to give acid 8-6 as a tan solid.
1 H NMR (300 MHz, CD3OD3) 8 7.96 211, 1=8Hz), 7.80 (mn, 1H), 7.33 2H, J=-8Hz), 6.84 I1H, J=9Hz), 6.69 I1H, J=7Hz), 3.09 (in, 4H).
Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyllbenzoyl-2(S)-(4-iodop2henyl sulfonvl amino)- 5 -alanine (8-7) A solution of acid 9- (400 mg, 1.43 mmol), amnine 8-4 (686 mg, 1.57 inmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mn-ol), NMM (632 p1, 5.72 inmol) and DMF (10 was stirred for ~20 h. The reaction was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAC 5% isopropanol/EtOAc) provided amnide 8-7 as a white solid.
TLC Rf 0.4 (silica, 10% isopropanol/EtOAc) IH NMR (300 MHz, CD3OD)) 8 7.79 2H, J=9Hz) 7.61 2H, J=8Hz), 7.52 2H, J=9Hz), 7.29 (in, 11H), 7.27 2H, J=8Hz), 4.20 (mn, 1H), 3.95 2H, J=7Hz), 3.66 (dd, 111, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (mn, 2H), 2.86 (mn, 2H), 1.08 3H, 1=7Hz).
WO 98/08840 PTU9/41 PCTIUS97/14912 -127 4- [2-(2-Aminopyridin-6-yl)ethyllbenzoyl-2(S)-(4-iodophenylsulfonyl amino)- D -alanine (8-8) A solution of ester 8-7 (200 mng, 0.3213 mmol) and 6N HCI (30 ml) was heated to 60 0 C. After -20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAcIEtOH/ NI-40H1H20) provided acid 8-8 as a white solid.
TLC Rf 0.45 (silica, 20:20: 1:1 EtOAcIEtOHINH4OHIH2O) I H NMR (400 MI-z, DMSO) 8 8.40 (in, 1H), 8.14 (Bs, LH), 7.81 2H, J=8Hz), 7.62 2H, 1=8Hz), 7.48 211, J=8Hz), 7.27 (in, 3H), 6.34 1H, J=7Hz), 6.25 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (in, 2H), 2.97 (in, 2H), 2.79 (mn, 2H).
4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S )-(4-trimethylstannylp2henylsulfonylainino-D-alanine (8-9) A solution of iodide 8 -8 (70 mg, 0. 1178 iniol), (CH3 Sn)2 (49 1.1, 0.2356 minol), Pd(PPh3)4 (5 mg) and dioxane (7 ml) was heated to 90 0 C. After 2 h, the reaction was concentrated and then purified by prep HPLC (Delta-Pak C 18 15 pM I100A', 40 x 100 mm; 95:5 5:95 H20/CH3CN) provided the trifluoroacetate salt. The salt was suspended in H20 (10 ml), treated with NH40.H (5 drops) and then lyophilized to provide amide 8-9 as a white solid.
I H NMR (400 MHz, DMSO) 8 8.40 (in, 1H), 8.18 IlH, J=8Hz), 7.67 (in, 5H), 7.56 2H, 1=8Hz), 7.29 2H1, J=8Hz), 6.95-7.52 (mn, 2H), 6.45 (bs, 2H), 4.00 (in, 1H), 3.50 (mn, 11H), 3.33 (in, 1H), 2.97 (in, 2H), 2.86 (mn, 2H).
4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-l 2 5 iodop-henylsulfonylamino-o-alanine (8-10) An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na 1 251 (Amersham, IMS3O) and stirred for five minutes at room temperature. A solution of 0.1 mng of 8-9 in 0.05 mL of H2S04/MNeOH was made and immediately added to the Na 1 25 lliodobead vial. After stirring for three minutes at room temperature, WO 98/08840 PCT[US97/14912 128 approximately 0.04-0.05 mL of NH40H was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for purification [Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitrile (TFA):H20 (0.1% TFA) to 90% acetonitrile TFA):H20 TFA) over minutes, 1 mL/min]. The retention time of 8-10 is 17 minutes under these conditions. Fractions containing the majority of the radioactivity were pooled, lyophilized and diluted with ethanol to give approximately 1 mCi of 8-10, which coeluted on HPLC analysis with an authentic sample of 8-8.
Instrumentation: Analytical and preparative HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC a Vydac peptide-protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column. The acetonitrile used for the HPLC analyses was Fisher Optima grade. The HPLC radiodetector used was a Beckman 170 Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x 250 mm was used for analytical and preparative HPLC. Solutions of radioactivity were concentrated using a Speedvac vacuum centrifuge.
Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 8452A UV/Vis Diode Array Spectrophotometer.
Sample radioactivities were determined in a Packard A5530 gamma counter.
WO 98/08840 PCT/US97/14912 -129- SCHEME9
H,
BocHN' 0 9-1 HCI, EtOAc, 000
HCI*
-9- N) N
H
NaCNBH 3 MeOH IBoc 2
THF
WO 98/08840 PCT/US97/14912 130- SCHEME 9 (Cont'd) 0 H>N OCH 3 N.BocO0 9- Pd/C EtOH 0 NN.-
OR
BocO0 9-6.R
=CH
3 NaOH 9-7, R= H EDC, HOBT, DMF 0 (H
N
N N COEt
NN
I H Boc 0 9-8 I6N HOI OlN H H/ AN> C02H 0 9-9 WO 98/08840 PCT/US97/14912 131 Methyl (S)-(3-amino-2-oxo-pyrrolidin-l-yl)-acetic acid hydrochloride(9-2) A solution of 9-1 (0.50 g, 1.84 mmol) (prepared as described by Freidinger, R. Perlow, D. Veber, D. J. Org.
Chem., 1982, 26, 104) in anhydrous ethyl acetate (50 mL) was cooled to 0°C and saturated with HCI gas, then stirred at 0°C for 2 h. The resulting colorless solution was concentrated at reduced pressure and the residue triturated with anhydrous diethyl ether giving 9-2 as a hygroscopic white solid.
IH NMR (300 MHz, CD 3 0D) 8 4.16 2H); 4.2 1H); 3.68 3H); 3.53 2H); 2.58 1H); 2.09 1H).
Methyl 2-oxo-3(S)-[ 1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-lyll-acetic acid (9-4) A solution of 9-2 (232 mg, 1.11 mmol) and 9-3 (176 mg, 1.11 mmol) (prepared as reported by Weissenfels, Ulrici, Z.
Chem. 1978, 18, 20.) in anhydrous methanol (10 mL) was treated with NaOAc (91 mg, 1.11 mmol) NaBH 3 CN (70 mg, 1.11 mmol) and powdered 4 A molecular sieves (450 mg). The resulting mixture was stirred at 0° for 3.5 h, then concentrated and the residue subjected to flash chromatography on silica gel (95:4.5:0.5 CH 2 CI2/MeOH/NH 4 0H) to afford 9-4 as a colorless glass.
FAB MS (315, M+1); 'H NMR (300 MHz, CD30D) 8 9.04 1H); 8.41 (dd, 1H); 8.38(d, 1H); 7.72 1H); 7.62 (dd, 1H); 4.31 2H); 4.21 2H); 3.68 (s, 3H);3.63 1H); 3.53 2H); 2.52 1H); 1.95 1H).
Methyl [3(S)-[tert-butoxycarbonyl-[1,8]naphthyridin-2-ylmethyl)amino -2-oxo-pyrrolidin- -yll-acetic acid A solution of amine 9-4 (69 mg, 0.22 mmol) in THF mL) was treated with Boc20 (83 mg, 0.24 mmol) and stirred at room temperature for 18 h. The solvent was removed in vacuo and the resulting residue isolated by chromatography on silica gel MeOH/CH2Cl2) to afford 9-5 as a yellow glass.
WO 98/08840 WO 988840PCT/US97/14912 -132- FAB MS (415, M+l); IH NMR (300 MHz, CD 3 OD) 8 9.04 1H); 8.20 (in, 2H); 7.88 (d, (rotamer 7.82 0.5H (rotamer 7.46(m, 1H); 5.1-4.3 (in, 5H); 3.81 (mn, 2H); 3.72 3H); 3.41 (in, 2H); 2.36 (mn, 2H); 1.47 4.5 H (rotamer 1.30 4.5 H (rotamner Methyl 3(S)-[tert-butoxycarbonyl-(5 ,6,7,8-tetrahydro- [1 ,8]naphthyridmn- 2-vlmethvl)-aminol -2-oxo-pyrrolidin- 1 -yll -acetic acid (9-6) A solution of 9-5 (40 mg, 0.O97mmol) in EtOH (5 ml-) was treated with 10% Pd on C (8 mg) and then stirred under a H2 filled balloon for 16 h. The catalyst was removed by filtration through celite and the filtrate concentrated to afford 9-6 as a colorless glass.
IH NMR (300 MHz, CD 3 OD) 8 7.10 1H) 6.78 0.5H (rotamer 6.62 0.5H (rotamer 4.8-3.9 (in, 5H); 3.81 (in, 2H); 3.72 3H); 3.3 8 (mn, 2H); 2.36 (in, 2H); 1.21 4.5 H (rotamer 1. 15 4.5 H (rotarner 3 [tert-butoxycarbonyl ,8 -tetrahy dro 1,8]naphthyri din -2ylmethyl)-aminol-2-oxo-pvrrolidin- 1 -vil-acetic acid (9-7) A solution of 9-6 (38 mg, 0.09 1 mnmol) in 50 aqueous THF (2 mL) was treated with 1.0 N NaOH (95 mL, 0.095 mmol) and stiffed at room temperature for 2 h. The reaction was nuetralized with 1N HCl, evaporated, and the residue dissolved in MeOH (2.5 inL), filtered and evaporated to afford 9-7 as a colorless glass.
IH NMR (300 MHz, CD 3 OD) 8 7.31 1H) 6.78 (br, d, IH); 4.8-3.9 (mn, 5H); 3.81 (in, 2H); 3.38 (mn, 2H); 2.36 (in, 2H); 1.21(s, 4.5 H (rotamer 1.15 4.5 H (rotainer Ethyl 3 ,6,7 ,8 -tetrahydro-[ 1,8]naphthyridin-2ylmethyl)-amino] -pyrrolidin- 1-yl I-acetylamino)-3 -(S)-pyridin-3 -yl- 1ro ~ionic acid (9-8) 9-7 (43 mng, 0.093 inmol), 1-9 (25 mng, 0093 inmol), EDC (18 ing, 0.093 inmol), HOBT (13 mg, 0.093 mmol), and N-methyl WO 98/08840 PCT/US97/14912 133morpholine (31 mL, 0.28 mmol) in anhydrous DMF (5 mL) was stirred at room temperature for 18 h, then concentrated in vacuuo and the residue chromatographed on silica gel using 5% MeOH/CH2C12 as eluent affording 9-8 as a colorless glass.
1H NMR (300 MHz, CDCI 3 5 8.61 1H); 8.45 1H); 8.00 1H); 7.68, 1H); 7.21 1H); 7.17 1H); 5.56 1H); 4.75 2H); 4.45 2H); 4.05 2H); 3.95 1H); 3.5-3.3 4H); 2.92 (m, 1H); 2.87 1H); 2.74 2H); 2.35 2H); 1.92 2H); 1.36 (s, 9H); 1.21 3H).
2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)amino]-pyrrolidin- 1-yl} -acetylamino)-3-(S)-pyridin-3-yl-propionic acid (9-9) 9-8 (25 mg, 0.043 mmol) was dissolved in 6 N HCI (2 mL) and stirred at room temperature for 16 h, then evaporated to afford 9-9 as a pale yellow solid.
FAB MS (453, M+1); IH NMR (300 MHz, CD30D) 8 9.00 1H); 8.81 1H); 8.79(m, 1H); 8.10 1H); 7.71 1H); 7.01 1H); 5.56 1H); 4.75 2H); 4.61 1H); 4.50 1H); 4.35 1H); 4.10 2H); 3.62 4H); 3.4 -3.0 2H); 2.8 2H); 2.70 1H); 2.45 (m 1H); 1.98 2H).
Following the procedure described in Scheme 10, bicyclic compounds such as 10-6 are readily prepared by one of ordinary skill in the art.
WO 98/08840 WO 988840PCTIUS97/14912 134
,OH
HNK
C0 2
H
10-1 (Fluka) 1. BOC 2 O, NEt3, DMF 2. DMF, 0S 2 00 3 Mel 3. Ts~l, pyridine 4. NaCN, DMSO, 70 0
C
NXCN
BOO' C0 2 0H 3 10-2 1. DMF, NaH, ethyl bromoacetate 2. NaOH, ethanol H"1 0 10-4
N
BOO
10-3 DMF, NEt 3 S2-10 1. HOI, EtOAc 2. NaCNBH 3
BOO
3. H 2 10% Pd/O, EtOH 4. NaOH, EtOH N N CHO 10-5
H
10-6 -WO 98/08840 PTU9/41 PCT/US97/14912 135 SCHEME11 0 INH PhOHO TsOH (cat.) LiN(iPr) 2
I
1-2 11-1 1 U2
H
2 Pd/C then TsOH (cat.)
HO
11-4 OH 11-3 Ph 3 P, 12 imidazole NaBH 4 11-5 0 0 11-6 Li/NH3j 0 0 NaN(Si(CH 3 3 2 Br }f 0
OH
3 iJ-- WO 98/08840 WO 988840PCT/US97/14912 136- SCHEME 11 (CONTUD Q~tacetone o TsOH (cat.) 11-8
OH
3 o 0 N NH 2 0H 1-4 0 0 11-10 OH
H
2 Pd/C -"NY OEt CH3 11-11 Jr 6N HCI 'N
>OH
CH3 11-2 WO 98/08840 PTU9/41 PCTIUS97/14912 -137- SCHEME 11 (CONT'D) EDO, HOBT
NMM
H2N~{ I NaOH 1114 WO 98/08840 PCT/US97/14912 138- 3 (R)-phenyl-tetrahydro-pvrrolo[ 1.2(S)-cloxazol-5-one (11-2) A mixture of alcohol (S)-5-(hydroxymethyl)-2pyrrolidinone (11-1, Fluka) (5.0 g, 43.4 mmol), benzaldehyde (5.7 mL, 56.4 mmol), p-TSA (80 mg, 0.4340 mmol) and toluene (125 mL) was heated to reflux with azeotropic removal of water for 18 hours. The solution was concentrated. Flash chromatography (silica, EtOAc/hexanes) gave 11-2 as a yellow oil.
TLC Rf 0.21 (silica,50% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 8 7.29 7.46 5H), 6.34 4.24 1H), 4.16 J=5.8 Hz, 1H), 3.49 J=7.8 Hz, 1H), 2.82 1H), 2.55 1H), 2.39 1.97 (m,lH).
6(S)-[2-(2-methyl-[ 1,3]dioxolan-2-yl)-ethyl]-3(R)-phenyl-tetrahydropyrrolo[ 1,2(S)-cloxazol-5-one (11-3) To a stirred solution of 11-2 (7.0 g, 34.4 mmol), HMPA (30.0 mL, 172 mmol) and THF (150 mL) at -78 0 C was added LDA (18.9 mL, 37.8 mmol, 2.0 M in heptane/THF). After 10 minutes, the reaction was warmed to -15 0 C. After 20 min, 1-2 (8.3 g, 34.4 mmol), dissolved in 10 mL of THF, was added. After 2 h, the reaction was warmed to ambient temperature for 3.0 hours and then recooled to for 18 hours. The reaction was warmed to ambient temperature for 2 hours and then diluted with Et 2 0, washed with H 2 0, dried (MgSO 4 and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 11-3 as an oil.
TLC Rf 0.28 (silica,50% EtOAc/hexanes) 1 H NMR (300 MHz, CDCI3) 5 7.25 7.46 5H), 6.33 4.24 1H), 4.11 1H), 3.95 4H), 3.52 J=7.3 Hz, 1H), 2.87 (m, IH), 2.57 1H), 2.10 (m,lH) 1.40 1.86 4H), 1.34 (s,3H).
1-benzyl-5(S)-hydroxymethyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)ethyll-pyrrolidin-2-one (11-4) A mixture of 11-3 (2.0 g, 6.30 mrol) and 10% Pd/carbon g) in EtOH (30 mL) was stirred under a balloon of hydrogen for h. Following filtration and evaporative removal of the solvent, the WO 98/08840 PCT/US97/14912 139residue dissolved in benzene (30 mL), treated with TsOH (10 mg) and ethylene glycol (1.05 mL, 18.9 mmol) and then heated to reflux with azeotropic removal of water for 1 hour. The reaction was concentrated.
Flash chromatography (silica, 70:23:7 CHCl3/EtOAc/MeOH) gave 11-4 as an oil.
1 H NMR (300 MHz, CDC13) 6 7.30 5H), 4.64 J=15 Hz, 1H), 4.25 J=15 Hz, 1H 3.95 4H), 3.72 1H), 3.49 2H), 2.46 1H), 2.15 2H), 1.74 1.53 (m,2H) 1.35 (s,3H).
1 -benzyl-5(S)-iodomethyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]pyrrolidin-2-one (11-5) To a stirred solution of 11-4 (2.0 g, 6.26 mmol), PPh 3 (2.63 g, 10.0 mmol), imidazole (725 mg, 10.6 mmol) and CH 3 CN mL) at 0°C was added 12 (2.39 g, 9.39 mmol) in five portions over minutes. After 20 minutes, the reaction was warmed to 50C for minutes and then poured into 200 mL 1:1 EtOAc/ hexanes. The solution was washed with 10% sodium bisulfite, sat NaHCO 3 brine, dried (MgSO 4 and concentrated. Flash chromatography (silica, EtOAc/hexanes) gave 11-5 as an oil.
TLC Rf 0.27 (silica,50% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 7.19 7.35 5H), 5.04 J=15.1 Hz, 1H), 3.96 5H), 3.30 (m 1H), 3.19 2H), 2.50 1H), 2.32 2.12 1.79 1.58 1.36 (m,4H).
1-benzyl-5(R)-methyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]pyrrolidin-2-one (11-6) To a stirred solution of 11-5 (900 mg, 6.26 mmol) and HMPA (30 mL) was added NaBH 4 (156 mg, 4.20 mmol). After minutes, the reaction was poured into 50 mL 1:1 Et20/ hexanes and then washed with H 2 0, brine, dried (MgS04) and concentrated to provide 11- 6 as an oil.
TLC Rf 0.34 (silica,50% EtOAc/hexanes) WO 98/08840 PCT[US97/14912 -140- IH NMR (300 MHz, CDC13) 6 7.20 7.33 5H), 4.95 J=15.1 Hz, 1H),4.03 J=14.9Hz, 1H), 3.95 (s 4H), 3.41 1H), 2.38 (m, 2H), 2.10 1.75 1.48 1.35 1.16 (m,4H).
5(R)-methyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2one (11-7) Into a 3-necked 500mL flask at -78 0 C was condensed 200 mL of ammonia. Lithium (64 mg, 9.25 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, 11-6 (560 mg, 1.85 mmol), dissolved in 25mL of THF, was added. After minutes, the reaction was quenched with NH 4 C1; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for 30 minutes to remove the ammonia. The solution was dried (MgSO 4 and concentrated. Flash chromatography (silica, EtOAc MeOH/ EtOAc) gave 11-7 as an oil.
TLC Rf 0.33 (silica, 10% MeOH/ EtOAc) 1H NMR (300 MHz, CDC13) 8 5.98 (br s, 1H), 3.94 4H), 3.67 (m 1H), 2.40 2H), 2.02 1H), 1.70 1.40 1.33 1.22 (m,4H).
{5(R)-methyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-2-oxopyrrolidin-1-yl -acetic acid ethyl ester (11-8) To a stirred solution of 11-7 (355 mg, 1.67 mmol) and THF (10 mL) at -78 0 C was added NaN(TMS)2 (1.83 mL, 1.83 mmol, 1.0 M in THF). After 20 min, ethyl bromoacetate (0.203 mL, 1.84 mmol) was added and the reaction was warmed to 0°C. After minutes, the reaction mixture was diluted with EtOAc and then washed with H20, brine, dried (MgSO4), and concentrated to give 11-8 as a yellow oil.
TLC Rf 0.90 (silica, 10% MeOH/ EtOAc) 1 H NMR (300 MHz, CDC13) 8 4.35 J=17.6 Hz, 1H), 4.18 J=7.1 Hz, 2H), 3.94 4H), 3.74 3H), 2.44 2H), 2.05 1H), 1.73 2H), 1.43 1H), 1.33 1.27 J=7.1Hz, 3H), 1.20 (d, J=6.4 Hz, 3H).
WO 98/08840 PCTfUS97/14912 -141- [5(R)-methyl-2-oxo-3(S)-(3-oxo-butyl)-pyrrolidin- I-yl]-acetic acid ethyl ester (11-9) A solution of 11-10 (360 mg, 1.20 mmol), p-TSA (10 mg) and acetone (20 mL) was heated at reflux for 1 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 11-9 as an oil.
TLC Rf 0.54 (silica, 1 H NMR (300 MHz, CDC13) 8 4.32 J=17.6 Hz, 1H), 4.18 (q, J=7.1Hz, 2H), 3.73 3H), 2.72 2H), 2.42 1H), 2.16 3H), 1.99 1H), 1.78 1H), 1.27 J=7.1Hz, 3H), 1.20 J=6.1 Hz, 3H).
[5(R)-methyl-3(S)-(2-[ 1,8]naphthyridin-2-yl-ethyl)-2-oxo-pyrrolidin-1yll-acetic acid ethyl ester (11-10) A mixture of 11-9 (220 mg, 0.8619 mmol), 1-4, 2-amino- 3-formylpyridine (137 mg, 1.12 mmol) and proline (99 mg, 0.8619 mmol) in absolute ethanol (5 mL) was heated at reflux for 12 h.
Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 11-10 as a yellow oil.
TLC Rf 0.37 (70:25:5 chloroform/ethyl acetate/MeOH).
1 H NMR (300 MHz, CDC13) 6 9.08 1H), 8.16 (dd, J=2Hz, 6 Hz 1H), 8.12 (d,J=8Hz, 1H), 7.46 2H), 4.33 J=17.5 Hz, 1H), 4.17 2H), 3.71 3H), 3.21 J=8.0 Hz, 2H), 2.54 2H), 2.39 (m, 1H), 2.02 1H), 1.35 1H), 1.26 J=7.1 Hz, 3H), 1.21 J=6.3 Hz, 3H).
{5(R)-methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2yl)-ethyll-pyrrolidin-1-vll-acetic acid ethyl ester (11-11) A mixture of 1-10 (250 mg, 0.7323 mmol) and Pd/carbon (250 mg) in EtOH (5 mL) was stirred under a balloon of hydrogen for 20 h. Following filtration and evaporative removal of the WO 98/08840 WO 9808840PCTIUS97/14912 -142solvent, the residue was chromatographed (silica gel, 70:25:5 chloroformn/ethyl acetate/MeOH to give 11I-11 as a colorless oil.
TLC Rf 0.25 (70:25:5 chloroform/ethyl acetate/MeOH).
I H NMR (300 MHz, CDCl3) 5 7.05 1H, J=7.3 Hz), 6.39 1H, J=7.3 Hz), 4.77 (br s, lH), 4.17 IlH, J=17.5 Hz), 4.15 (in, 2H), 3.71 (mn, 2H), 3.39 (in, 2H), 2.64 (in, 4H), 2.46 (in, 2H), 2.30 (mn, 1H), 1.91 (in, 2H), 1.88 (in, lH), 1.26(t, 3H, J=6.1 Hz) 1.23 1.19 (d, J=6.4Hz, 3H).
t 5(R)-methyl-2-oxo-3 ,6,7 ,8-tetrahydro-[ 1,8]naphthyridin-2vl)-ethyll-pvrrolidin-l I-acetic acid hydrochloride (11-12) A mixture of 11I-11I(185 mg, 0.5356 mmol) and 6N HCI mL) was heated at 600 C for 1 h. Evaporative removal of the solvent gave 1- 12 as a yellow solid.
111 NMR (300 MHz, CD 3 OD) 8 7.59 I1H, J=7.3 Hz), 6.66 I1H, J=7.3 Hz), 4.17 12H, J= 17.8, Hz), 3.90 I1H, J= 17.8, Hz), 3.77 (in, 1H), 3.50 J=5.4 Hz, 2H), 3.31 (in, 4H), 2.52 (in, 2H), 2.25 (in, 1H), 1.95 2H, J=6.6 Hz), 1.80 (in, IRH), 1.34 (in, IlH), 1.25 J=6.3 Hz, 3H) 2-Oxo-5(R)-inethyl-3 ,6,7 ,8 -tetrahydro 1,8] -naphthyridin-2-yl)ethylip~yrrolidin- 1 -yl)acetyl-3(S)-alkvny1-o-alanine ethyl ester (11- 13) A mixture of 11I- 12 (350 mg, 0.9892 minol), Z-9 (193 ing, 1.09 inmol), EDC (378 mg, 1.98 mmcnl), HOBT (134 mg, 0.9892 inmol) and NMM 10 inL, 7.91 rnmol) in CH3CN (5 inL) was stirred for 20 h. The mixture was diluted with ethyl acetate, washed with sat.
NaHCO 3 brine, and dried over MgSO 4 Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH to give 1- 13 as a colorless foam.
TLC Rf 0.15 (70:25:5 chloroformn/ethyl acetate/MeGH).
1 H NMR (300 MHz, CDCl3) 5 7.05 (in, 2H), 6.39 1H, J=7.3 Hz), 5.04 (mn, 1H), 4.16 2H, J=7.lHz), 3.90 2H4), 3.64 (in, 1H),3.39 (in, 2H), 2.69 (in, 6H), 2.47 (in, 2H), 2.30 (mn, 11H), 1.90 (mn, 2H), 1.64 (in, 2H), 1.20 (mn, 7H).
WO 98/08840 PTU9/41 PCTIUS97/14912 143 2-Oxo-5(R)-methyl-3(S)-[2-(5 ,6 ,7,8-tetrahydro[ 1 -naphthyridin-2vl)ethvllpvrrolidin- 1 -yl)acetyl-3 (S)-alkynyl-fD-alanine (11- 14) To a solution of 11I- 13 (70 mg, 0. 1589 mmol) in EtOH (1 mL) was added IN NaOH (0.175 ml, 0.164 inmol). After stirring for 1 hi, the solvents were evaporated and the residue was chromatographed (silica gel, 25: 10: 1:1 to 15: 10: 1: 1 ethyl acetatelEtOH/water/Nl-40H to give 11-14 as a colorless foam.
TLC Rf 0.21 (10: 10: 1:1 ethyl acetatelEtOH/water/NH4OH).
1 H NMR (300 MHz, CD 3 OD) 8 7.42 I1H, J=7.3 Hz), 6.49 I1H, J=7.3 Hz), 4.35 (d,J=17.1 Hz, 1H), 3.64 (in, 3.50 (in, 3.18 (in, 2H), 2.77 J=5.6 Hz, 2H), 2.55 (in, 5H), 2.23 (mn, 1H), 1.91 (in, 4H), 1.41 (mn, 1H) 1.28 J=6.3 Hz, 3H-).
WO 98/08840 WO 988840PCT/US97/14912 -144- SCHEME 12 0 \-0 0 0 .IA OH
CH
3 0 0 0 0=s=O pyridine 121TsO Li 2 CU(Ph) 2 Li/NH3j 2-2 NaN(Si(CH 3 3 2 Br 0 0 0 Qy Et 0 12-4 P 00 II~~,NOEt 0 12-5 -Ph acetone TsOH (cat.) WO 98/08840 WO 9808840PCTIUS97/14912 -145- SCHEME 12 (CONT'D) 0 '1 1 12-5 NY NH 2 1-4 proline (cat.) 0 I .N~OEt N N y 0 12-6 ~Ph
H
2 Pd/C 0 N Et 0 ~Ph 12-7 6N HCI
C
~Ph 12-8 WO 98/08840 PCTIUS97/14912 -146- SCHEME 12 (CONT'D 'N jfyOH 0 EDO, HOBT
NMM
H
2 N OEt 0 N~N *2HCI 2-10 Ph 12-9 NaCH 12-10 WO 98/08840 PTU9/41 PCTIUS97/14912 147 1 -benzyl-5 (S )-methyl-p-toluenesulfonate-3 (S )-[2-(2-methyldioxolan-2-yl')-ethvll -pvrrolidin-2-one (12-1') To a stirred solution of 11 -4 (1.8 g, 5.63 mmol) and THF mL) at 0 0 C was added NaH (248 mg, 6.19 mmol). After minutes, TosCi was added followed by the removal of the cooling bath.
After 1.0 hour, the reaction was diluted with EtOAc and then washed with H 2 0, sat NaHCO 3 brine, dried (MgSO 4 and concentrated. Flash chromatography (silica, 40 60% EtOAc/hexanes) gave 12-1 as an oil.
TLC Rf 0.75 (silica, EtOAc) 1 H NMR (300 MHz, CDCI3) 8 7.72 J=8.30 Hz, 2H), 7.35 J=7.3 Hz, 2H), 7.25 (in, 3H), 7.09 (m 2H1), 4.94 J= 14.9 Hz, I1H), 4.01 (in, 1H), 3.94 3.83 J=15.1 Hz, lH), 3.54 2.46 (s,3H), 2.42 2.21 (in, IH), 2.01 (mn, 1H), 1.72 2H), 1.43 (in, 2H), 1.32 3H).
1 -benzyl-5(S)-benzyl-3 [2-(2-methyl- [1,3 ]dioxolan-2-yl)-ethyl] pvyrrolidin-2-one (12-2) To a stirred suspension of Cul (2.57 g, 13.5 inmol) and Et 2 O (10 mL) at 0 0 C was added PhLi (14.2 mL, 25.6 inmol, 1.8 M cyclohexane-ether) dropwise over a 1.0 hour period. After an additional hour, 12-1 (1.4 g, 2.96 minol), dissolved in 10 mL Et 2 O, was added. The reaction was stirred at -15'oC for 96 hours. The reaction was diluted with EtOAc and then washed with sat NH 4 CI, sat NaHCO 3 brine, dried (MgSO 4 and concentrated. Flash chromatography (silica, 30 -4 60% EtOAc/hexanes) gave 12-2 as an oil.
TLC Rf 0.29 (silica,50% EtOAc/hexanes)
I
1 H NMR (300 MHz, CDCl3) 8 7.13 7.36 (in, 8H), 7.02 J=7.6Hz, 2H), 5.06 J=14.9 Hz, 1H), 4.14 J=15.1 Hz, 1H), 3.95 (in, 4H), 3.55 (mn, 1H), 3.18 (dd, J=4.2, 17.0 I-z,1H), 2.35 2.04 (m,2H), 1.66 1.32 WO 98/08840 PCTIUS97/14912 148 5(S)-benzyl-3(S)-[2-(2-methyl-[ 1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2one (12-3) Into a 3-necked 500mL flask at -78 0 C was condensed 100 mL of ammonia. Next, 12-2 (470 mg, 1.24 mmol), dissolved in of THF, was added. Lithium (19 mg, 2.48 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, the reaction was quenched with NH 4 C1; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for minutes to remove the ammonia. The solution was dried (MgSO 4 and concentrated. Flash chromatography (silica, EtOAc) gave 12-3 as an oil.
TLC Rf 0.22 (silica, EtOAc) 1 H NMR (300 MHz, CDC13) 8 7.18 7.35 5H), 5.43 (br s, 1H), 3.95 4H), 3.92 (m 1H), 2.88 (dd, J=5.3, 18.6 Hz, 1H), 2.41 2H), 2.03 1.71 1.43 1.33 (s,3H).
(5(S)-benzyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-2-oxopyrrolidin-1-yl }-acetic acid ethyl ester (12-4) To a stirred solution of 12-3 (210 mg, 0.7257 mmol) and THF (5 mL) at -78 0 C was added NaN(TMS)2 (0.943 mL, 0.943 mmol, M in THF). After 30 min, ethyl bromoacetate (0.104 mL, 0.9434 mmol) was added and the reaction was warmed to 0°C. After 1.0 hour, the reaction mixture was diluted with EtOAc and then washed with sat NaHCO 3 brine, dried (MgSO4), and concentrated to give 12-4 as a yellow oil.
TLC Rf 0.64 (silica, EtOAc) 1H NMR (300 MHz, CDC13) 8 7.15 7.33 5H), 4.40 J=17.8 Hz, 1H), 4.15 2H), 3.93(m, 5H), 3.77 J=17.8, 1H), 3.07 (dd, J=5.0, 18.6 Hz, 1H), 2.56 1H), 2.39 1H), 2.20 (m, 1H), 2.05 1.69 2H), 1.23 -4 1.46 (m,8H).
[5(S)-benzyl-2-oxo-3(S)-(3-oxo-butyl)-pyrrolidin-l-yl]-acetic acid ethyl ester (12-5) A solution of 12-4 (260 mg, 0.6925 mmol), p-TSA (10 mg) and acetone (20 mL) was heated at reflux for 1 hr. NaHCO 3 was added WO 98/08840 PCTfUS97/14912 149to the cooled reaction mixture and then the mixture was concentrated.
The residue was diluted with CHCl 3 and then washed with brine, dried (MgSO4), and concentrated to afford 12-5 as an oil.
TLC Rf 0.66 (silica, 1 H NMR (300 MHz, CDC13) 8 7.22 7.36 3H), 7.15 J=6.5 Hz, 2H), 4.37 J=17.6 Hz, 1H), 4.18 2H), 3.97 1H), 3.77 (d, J=17.8 Hz, 1H), 3.06 (dd, J=5, 18 Hz, 1H), 2.60 3H), 2.42 1H), 2.17 1H), 2.14 3H), 1.96 1.74 1H) 1.27 4H).
[5(S)-benzyl-3(S)-(2-[1,8]naphthyridin-2-yl-ethyl)-2-oxo-pyrrolidin-1vll-acetic acid ethyl ester (12-6) A mixture of 12-5 (230 mg, 0.6940 mmol), 1-4, (2-amino- 3-formylpyridine, 110 mg, 0.9022 mmol) and proline (80 mg, 0.6940 mmol) in absolute ethanol (10 mL) was heated at reflux for 18 h.
Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/MeOH) to give 12-6 as a yellow oil.
TLC Rf 0.38 (70:25:5 chloroform/ethyl acetate/MeOH).
1 H NMR (300 MHz, CDC13) 8 9.08 1H), 8.16 (dd, J=2Hz, 10 Hz 1H), 8.09 (d,J=8.3 Hz, 1H), 7.44 2H), 7.28 2H), 7.16 J=8Hz, 2H), 4.37 J=17.6 Hz, 1H), 4.16 2H), 3.96 1H), 3.80 J= 17.6 Hz, 1H), 3.15 2H), 3.06 (dd, J=5.3, 18.5, 1H), 2.26 -4 2.63 4H), 1.97 1H), 1.47 1H), 1.25 J=7.1 Hz, 3H).
{5(S)-benzyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)ethyll-pyrrolidin-1 -yl -acetic acid ethyl ester (12-7) A mixture of 12-6 (220 mg, 0.5270 mmol) and Pd/carbon (100 mg) in EtOH (4 mL) was stirred under a balloon of hydrogen for 2 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH to give 12-7 as a colorless oil.
TLC Rf 0.25 (70:25:5 chloroform/ethyl acetate/MeOH).
1 H NMR (300 MHz, CDC13) 5 7.26 3H), 7.16 J=8.1Hz, 2H), 7.04 J=7.3 Hz, 1H), 6.36 J=7.3 Hz, 1H), 4.74 (br s, 1H), 4.39 (d, WO 98/08840 WO 988840PCTIUS97/14912 -150- J= 17.8 Hz, I1H), 4.15 (in, 2H), 3.90 (in, I1H), 3.77 J= 17.5 Hz, I1H), 3.38 (in, 2H), 3.06 (dd, J=2.4, 18.8 Hz, 1H), 2.65 (in, 5H), 2.43 (in, 1H), 2.22 (in, 3H), 1.89 (in, 1H) 1.36 (m,1Hi), 1.26 J=7.1 Hz, 3H).
5(s)-benzyl-2-oxo-3 ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)ethyl l-pyrro lidin- Il-yl I -acetic acid hydrochloride (12-8) A mixture of 12-7 (150 mg, 0.3559 inmol) and 6N HCI mL) was heated at 600 C for 1 h. Evaporative removal of the solvent gave 12-8 as a yellow solid.
1 H NMR (300 MHz, CD 3 OD) 8 7.57 J=7.3 Hz, I1H), 7.24 (in, 6.60 J=7.3 Hz, I1H), 4.24 J= 17.8, Hz, I1H), 4.03 (in, 2H), 3.49 (t, J=5.6 Hz, 2H), 3.15 (dd, 1=4.4, 17.6 Hz, 1 2.71 (in, 5H), 2.46 (in, 1H), 2.21 (in, 1H), 1.97 1.64 (in, 1H), 1.45 (m,1H) 2-Oxo-5(S)-benzyl-3(S)- ,6,7,8-tetrthydro -naphthyridin-2-yl)ethvllpvrrfolidin- 1 -l)acetyl-3(S )-pvridin-3 -yl-o-alanine ethyl ester (12-9) A mixture of 12-8 (150 mg, 0.3559 inmol), 2-10 (60 mg, 0.2135 mmol), EDC (132 mg, 0.7118 mmuol), HOBT (48 mg, 0.3559inmo1) and NMM (0.4 mL, 2.85 nimol) in DMF (4 mL) was stirred for 20 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO 3 brine, and dried over NMgSO 4 Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20: 10 chloroformn/ethyl acetate/MeOH to give 12-9 as a colorless foam.
TLC Rf 0. 15 (70:25:5 chloroformn/ethyl acetate/MeOH).
IH NMR (300 MHz, CD 3 OD) 8 8.55 1H), 8.44 (in, 1H), 7.82 (in, 1H), 7.6-7.1 (in, 7H), 6.33 J=7.5 Hz, 1H), 5.40 J=8 Hz, 1H), 4.2- 3.8 (mn, 6H), 3.38 (mn, 1H), 3.17 (in, 2H), 2.90 (in, 2H), 2.67 (mn, 2H), 2.54 (mn, 2H), 2.12 (mn, 2H),1.84 (in, 2H), 1.43 (in, 2H) 1.18 (mn, 3H).
2-Oxo-5(S)-benzyl-3 ,6,7 ,8-tetrahydro -naphthyridin-2vl)ethyllpyrrolidin- 1 -vlacetyl-3(S)-p2yridin-3-yl-o-alanine (12-13) To a solution of 12-9 (70 mg, 0. 1229 inmol) in EtOH (I mL) was added IN NaOH (0.150 ml, 0.150 nimol). After stirring for -WO 98/08840 PCTIUS97/14912 151 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25: 10: 1:1 to 15: 10: 1:1 ethyl acetate/EtOH/water/NH4OH to give 12- 10 as a colorless foam.
TLC Rf 0.21 (10:10:1:1 ethyl 1 H NMR (300 MHz, CD 3 OD) 5 8.62 I1H), 8.3 6 (in, I1H), 7.92 (in, 1H), 7.45-7.2 (mn, 7H), 6.49 J=7.1 Hz, LH), 5.27 (in, 1H), 4.31 (d, J=17.3 Hz, 1H), 3.93 (in, lH), 3.72 J=17.5 Hz, 1H), 3.30 (in, 3H), 2.92 -2.52 (mn, 8H), 2.36 (mn, 2H), 1.90 (in, 3H), 1.57 (mn, 1H).
WO 98/08840 PTU9/41 PCTIUS97/14912 152 SCHEM.E13
H
2 Pd/C Ph 3 P, 12 imidazole 1-1 11-2 NaBH 4 Li N (iPr) 2
CH(CH
3 2
N
3 S CH(CH 3 2
CH(CH
3 2 NaOEt 13-4
H
2 Pd/C, TFA then
BOC
2 O, NEt: 3
(H
3
C)
3 C -o
H
13-6 WO 98/08840 WO 9808840PCT/US97/14912 153 SCHEME 13. CONT'D
(H
3
C)
3
C
13-6
'OH
3 NaN(Si(CH 3 3 2 ~'Li/NH 3 (l 0
(H
3
C)
3 C O (HI 3 0) 3
C
13-7 Br OEt 0 13--a 0
(H
3
C)
3
C-A
NaOH 'OH 3 0 EDC, HOBT
NMM
(H
3
C)
3 C WO 98/08840 WO 988840PCTIUS97/14912 -154- SCHEME 13 (CONT'D) 0
(H
3
C)
3
C-A
CH3 13-10
HOI
H
3
N
CO
O~t CH3 13-11 NaB(O 2
CCH
3 3
H
,OEt I NaOH 13-13 WO 98/08840 PCT/S9714912 155 1-benzvl-5(S)-hydroxvmethyl-pyrrolidin-2-one (13-1) A mixture of 11-2 (5.0 g, 24.6 mmol), 10% Pd/C (2.5 g), and ethanol (80 mL) was stirred at ambient temperature under a hydrogen atmosphere (1 atm) for 5 hr. The catalyst was removed by filtration through a celite pad and the filtrate concentrated to give 13-1 as a colorless oil.
TLC RF 0.55 (silica, 70:20:10 CHCl3/EtOAc/CH30H); 1H NMR (300 MHz, CDC13) 8 7.29 5H), 4.83 2H, J=15H), 4.25 1H, J=15Hz), 3.77 1H), 3.51 2H), 2.54 1H), 2.40 (m, 1H), 1.92 2H).
1-benzyl-5(S)-iodomethyl-pyrrolidin-2-one (13-2) To a solution of 13-1 (18.5 g, 90.1 mmol), triphenylphosphine (40.1 g, 153 mmol), and imidazole (11.03 g, 162 mmol) in 225 mL of acetonitrile and 150 mL of ether at OC was added iodine (34.3 g, 135 mmol) in 5 portions over 5 minutes. After minutes, the reaction was heated to 50C, and a stream of argon passed over the reaction to purge the evaporating ether. After an additional minutes, the mixture was diluted with ether, the organic layer washed with NaHCO 3 (sat.) and brine, dried over K 2 CO3, and the solvent evaporated. Flash chromatography of the residue (silica, 7-15% EtOAc/
CHC
3 gave 13-2 as a yellow oil.
TLC Rf 0.53 (silica, 30% EtOAc/CHCI 3 IH NMR (300 MHz, CDC13) 8 7.31 5.05 1H, J=15Hz), 3.92 1H, J=15Hz), 3.41 1H), 3.26 2H), 2.62 1H), 2.43 (m, 1H), 2.16 1H), 1.81 1H).
methyl-pyrrolidin-2-one (13-3) To a solution of 13-2 (22.1 g, 70 mmol) in 200 mL of hexamethylphosphorous triamide at OC was added NaBH 4 (5.25 g, 140 mmol) in 5 portions over 5 minutes. After 10 minutes, the reaction was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with 1:1 ether/hexanes, quenched by the careful WO 98/08840 PCT/US974912 -156 addition of 300 mL 10% KHSO 4 separated, the organics dried over
K
2 C0 3 and the solvent evaporated to give 13-2 as a yellow oil TLC Rf 0.45 (silica, 30% EtOAc/CHC1 3 1H NMR (300 MHz, CDC13) 8 7.32 5H), 4.95 1H, J=15Hz), 4.00 1H, J=15Hz), 3.52 1H), 2.46 2H), 2.15 1H), 1.60 (m, 1H), 1.16 3H, 3(R)-azido-l-benzyl-5(R)-methvl-pyrrolidin-2-one (13-4) To a solution of 13-3 (2.2 g, 11.6 mmol) in THF (45 mL) at -78° C was added a solution of LDA (6.39 mL, 12.8 mmol; 2M/THF,ethylbenzene). The mixture was warmed to -15 0 C for minutes, then recooled to -78 0 C, and 2,4,6-triisopropylbenzenesulfonyl azide (4.31 g, 13.9 mmol, prepared as described in Harmon, et al, J.
Org. Chem. 1973, 38, 11-16.) was added rapidly as a solution in 40 mL THF at -78 0 C. After 10 minutes, glacial acetic acid (2.67 mL, 47 mmol) was added, and the resultant viscous liquid mixture allowed to warm to ambient temperature and stir for 1 hour. The solvent was then evaporated, the residue dissolved in CHCI 3 washed with NaHCO 3 (sat.), and dried over magnesium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 25% ethyl acetate/hexanes) to give 13-4 as a colorless oil.
TLC Rf 0.38 (25% ethyl acetate/hexanes).
1 H NMR (300 MHz, CHC13) 8 7.32 5H), 5.00 1H, J=15 Hz), 4.27 1H, J=7.5 Hz), 3.98 1H, J=15 Hz), 3.54 1H), 1.97 (m, 2H), 1.16 3H, J=6.0 Hz).
3(S)-azido-1 -benzvl-5(R)-methyl-pyrrolidin-2-one To a solution of 13-4 (2.17 g, 9.42 mmol) in EtOH mL) was added a solution of NaOEt (3.52 mL, 9.42 mmol; 2.68 M/EtOH). The mixture was stirred for 90 minutes, then quenched by the addition of glacial acetic acid (3 mL). The solvent was then evaporated, the residue slurried in EtOAc, washed with NaHCO 3 (sat.), and dried over K 2
CO
3 Following evaporative removal of the solvent, WO 98/08840 PCTftJS97/14912 157 the residue was chromatographed (silica gel, 17% ethyl acetate/hexanes) to give 13-5 as a colorless oil and 13-4 as a colorless oil.
TLC Rf 0.44 (25% ethyl acetate/hexanes).
1H NMR (300 MHz, CHC13) 8 7.32 5H), 4.97 (d,lH, J=15 Hz), 4.17 1H, J=7.5 Hz), 4.05 1H, J=15 Hz), 3.44 1H), 2.48 2H), 1.50 1H), 1.22 3H, J=6.6 Hz).
(1-benzyl-5(R)-methyl-2-oxo-pyrrolidin-3(S)-yl)-carbamic acid tertbutvl ester (13-6) A mixture of 13-5 (2.38 g, 10.3 mmol), 10% Pd/C (1.0 g), TFA (10 mL), THF (80 mL) and methanol (100 mL) was stirred at ambient temperature under a hydrogen atmosphere (1 atm) for 3 hr.
The catalyst was removed by filtration through a celite pad and the filtrate concentrated to give the intermediate amine salt as a colorless oil. To a solution of the crude amine salt in THF (50 mL) at o0C was added NEt 3 (2.88 mL, 20.7 mmol) and di-tert-butyl dicarbonate (2.59 g, 11.9 mmol). The mixture was allowed to warm to ambient temperature and stir for 4 hours. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40% ethyl acetate/hexanes) to give 13-6 as a colorless oil.
TLC RF 0.44 (silica, 40% ethyl acetate/hexanes); 1H NMR (300 MHz, CHC13) 8 7.31 5H), 5.17 (br s, IH), 4.94 (d, 1H, J=15 Hz), 4.20 1H), 4.07 IH, J=15 Hz), 3.44 1H), 2.77 IH), 1.45 9H), 1.20 3H, J=7 Hz).
(5(R)-methyl-2-oxo-pyrrolidin-3(S)-yl)-carbamic acid tert-butyl ester (13-7) To a blue solution of lithium metal (0.237 g,34.2 mmol) in
NH
3 (200 mL) at -78 0 C was added a solution of 13-6 (2.60 g,8.54 mmol) in THF (15 mL). The mixture was stirred for 15 minutes, then quenched by the addition of ammonium chloride until the blue color dispersed. An additional 30 mL of THF was added, and the mixture warmed to 35 0 C to evaporate the ammonia. MgSO4 was added,the mixture was filtered through a celite pad. Following evaporative WO 98/08840 PCT/US97/14912 158 removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH) to give 13-7 as a colorless oil TLC Rf 0.45 (70:20:10 chloroform/ethyl acetate/MeOH).
1 H NMR (300 MHz, CHC13) 8 6.97 (br s, 1H), 5.24 (d,lH, J=7.6 Hz), 4.32 (br s, 1H), 3.66 1H), 2.79 1H), 1.45 9H), 1.25 3H, Hz).
(3(S)-tert-butoxycarbonylamino-5(R)-methyl-2-oxo-pyrrolidin-1-yl)acetic acid ethyl ester (13-8) To a solution of 13-7 (1.83 g, 8.4 mmol) in THF (22 mL) at -78° C was added sodium bis(trimethylsilyl)amide (9.4 mL, 9.4 mmol; 1 M/ THF) dropwise. After an additional 20 min, ethyl bromoacetate (1.13 mL, 10.3 mmol) was added dropwise. After an additional 20 minutes, the mixture was allowed to warm to 0°C, and mL sat. aqueous NH4CI was added. The layers were separated, the aqueous layer washed with EtOAc, and the combined organic extracts were dried over K 2 C0 3 Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40% ethyl acetate/hexanes) to give 13-8 as a colorless oil.
TLC Rf 0.39 (40% ethyl acetate/hexanes).
1 H NMR (300 MHz, CHC13) 6 5.20 (br s, 1H), 4.38 (d,lH, J=18 Hz), 4.21 3H), 3.77 2H), 2.83 1H), 1.44 9H), 1.23 6H).
(3(S)-tert-butoxycarbonylamino-5(R)-methyl-2-oxo-pyrrolidin-1-yl)acetic acid (13-9) To a solution 13-8 (527 mg, 1.75 mmol) in EtOH was added IN NaOH (1.93 mL, 1.925 mmol). After stirring for 1 h, the solvents were evaporated, the mixture was diluted with EtOAc, acidified with 10% KHSO 4 washed with brine, dried over MgSO 4 and evaporated to give 13-9 as a white solid.
TLC Rf 0.48 (silica,9.5/0.5/0.5 CH 2
CI
2 /MeOH/AcOH) IH NMR (300 MHz, CD30D) 8 4.21 2H), 3.85 1H, J=18 Hz), 3.74 1H), 2.58 1H), 1.52 1H), 1.44 9H), 1.25 J=6.3 Hz, 3H).
WO 98/08840 PCTIUS97/14912 159- (3(S)-tert-butoxycarbonylamino-5(R)-methyl-2-oxo-pyrrolidin- 1-yl)acetyl-3(S)-alkynyl-P-alanine ethyl ester (13-10) A mixture of 13-9 (440 mg, 1.62 mmol), 2-9 (290 mg, 1.62 mmol), EDC (373 mg, 1.94 mmol), HOBT (262 mg, 1.94 mmol) and NMM (1.20 mL, 11.34 mmol) in CH3CN (5 mL) was stirred for h. The mixture was diluted with EtOAc, washed with sat. NaHCO 3 brine, and dried over MgSO 4 Following evaporative removal of the solvent, the residue was chromatographed (silica gel, EtOAc) to give 13-10 as a colorless foam.
TLC Rf 0.20 (silica, EtOAc).
1 H NMR (300 MHz, CDC13) 8 7.31 (bd, 1H), 5.33 (bd, 1H), 5.21 (m, 1H), 4.16 5H), 3.64 2H), 2.72 2H), 2.45 J=2.2 Hz, 1H), 1.52 1H), 1.46 9H), 1.27 6H).
(3(S)-amino-5(R)-methyl-2-oxo-pyrrolidin-I -yl)-acetyl-3(S)-alkynyl-Palanine ethyl ester hydrochloride (13-11) To a solution of 13-10 (550 mg, 1.39 mmmol) in EtOAc at 0°C was bubbled HC1 gas for 5 minutes. The reaction was stirred an additional 5 minutes, followed by removal of the cooling bath and then purged with Argon for 20 minutes. Evaporative removal of the solvent gave 13-11 as a white solid.
1 H NMR (300 MHz, CD30D) 8 5.02 1H), 4.12 4H), 3.83 (m, 2H), 2.77 2H), 1.59 1.25 6H).
5(R)-methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2ylmethyl)-amino]pyrrolidin-1 -yl)acetyl-3(S)-alkynyl-3-alanine ethyl ester (13-12) To a soution of 13-11 (450 mg, 1.39 mmol) and 5,6,7,8tetrahydro-[1,8]naphthyridine-2-carbaldehyde (225 mg, 1.39 mmol) in dichloroethane at 0°C was added Na(OAc) 3 BH. After 1.5 h the reaction was quenched with sat. NaHCO 3 diluted with EtOAc, washed with sat.
NaHCO 3 brine and dried over MgSO 4 Following evaporative removal WO 98/08840 PTU9/41 PCTIUS97/14912 160 of the solvent, the residue was chromatographed (silica gel, 70:20: chloroform/ethyl acetate/MeOH to give 13-12 as a colorless foam.
TLC Rf 0.17 (70:15:15 chloroform/ethyl acetate/MeOH).
I
1 H NMR (300 MHz, CDCI3) 8 7.09 J=6.8 Hz, IlH), 7.03 Hz, I1H), 6.48 J=7.3 Hz, I1H), 5.05 (in, IlH), 4.83 (bs, I1H), 4.17 (q, J=6.4, 1H), 3.92 (in, 2H), 3.74 (in, 2H), 3.58 (in, 4H), 3.40 (in, 2H), 2.70 (in, 4H), 2.54 (in, IH), 2.26 1H), 1.90 (in, 2H), 1.55 (in, 2H), 1.25 (in, 6H).
5(R)-methyl-2-oxo-3(S)- ,8-tetrahydro[l1,8] -naphthyridin-2ylmethyl)-aminolpvrrfolidin- 1 -l)acetvl-3 (S)-alkynvl-o3-alanine (13-13) To a solution of 13-12 (108 mg, 0.24 rnmol) in EtOH (2 mL) was added 1N NaOH (0.270 ml, 0.264 mmol). After stirring for 1 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25: 10: 1:1 to 15: 10: 1:1 ethyl acetate/EtOH/water/NIH4OH) to give'13-13 as a colorless foamn.
TLC Rf 0.23 (12: 10: 1:1 ethyl acetatefEtOH/waterfNH4OH).
1 H NMR (300 MHz, D 2 0) 8 7.53 I1H, J=7.3 Hz), 6.69 1H, J=7.3 Hz), 4.41 (in, 2H), 3.71 (in, 2H), 3.45 J=5.8 Hz, 2H), 2.79 J=5.8 Hz, 2H), 2.6 (mn, 4H), 1.92 (in, 3H), 1.50 (in, LHI), 1.19 (in, 3H).
SCHEME 14 0 0
H
2 10% Pd/C HO0 EtOH N N N' NH 2 cat. praline 1 4-1 0- 1-4 MeOH, reflux C I ~TFA C NCH0 N~ NN- CHOH NH N4 H 1 4 3 WO 98/08840 PCT/US97/14912 161 2-Dimethoxymethyl-[ 1.81naphthyridine (14-1) A mixture containing 1-4 (30 g, 0.245 mol), pyruvaldehyde dimethylacetal (87 g, 0.737 mol), and L-proline 0.062 mol) in MeOH (300 mL) was refluxed under argon for 16 h.
The cooled solution was filtered, evaporated and the residue dissolved in
CH
2 C1 2 (500 mL) and washed with water and brine then dried and concentrated to a volumn of ca. 100 mL. Hexane (300 mL) was added and the mixture was kept at o0C for 3 h, then filtered affording 14-1 as an off-white crystalline solid.
'H NMR (300 MHz, CDCIl) 8, 9.14 J 2.2 Hz, 1H); 8.26 J 8.7 Hz, 1H); 8.21 (dd, J 8.7, 2.2 Hz, 1H); 7.8 J 8.3 Hz, 1H); 7.5 (m, 1H); 5.48 1H); 3.53 6H).
2-Dimethoxymethyl-5,6.7.8-tetrahydro-[1.8lnaphthyridine (14-2) A solution 14-1 (10 g, 0.049 mol) in MeOH, (100 ml) was treated with 10% Pd on C (1.5 g) and the resulting mixture stirred under a H 2 filled balloon for 12.5 h. The catalyst was removed by filtration through celite and the solution concentrated to afford 14-2 as a yellow crystalline solid.
'H NMR (300 MHz, CDCI 3 7.18 J 7.12 Hz, 1H); 6.71 J 7.12 Hz, 1H); 5.18 1H); 4.96 (br, s, 1H); 3.43 6H); 3.4 2H); 2.65 2H); 1.91 2H).
5.6,7,8-tetrahydro- 1.81naphthyridine-2-carboxaldehyde (14-3) 14-2 (10 g, 0.048 mol) was trifluoroacetic acid (50 mL) and the resulting solution stirred under argon for 12.5 h. The TFA was removed at reduced pressure and the residue partitioned between sat. NaHCO3 and CH 2 C1 2 The organic layer was dried, concentrated and passed through a 3 in. pad of silica gel (10% acetone/CH 2 Cl 2 and concentrated to afford 14-3 as a yellow crystalline solid.
'H NMR (300 MHz, CDCI 3 8 9.80 1H); 7.31 J 7.32 Hz, 1H); 7.16 J 7.32 Hz, 1H); 5.31 (br, s, 1H); 3.48 2H); 2.81 2H); 1.94 2H).
WO 98/08840 PTU9/41 PCT/US97/14912 162 OEt Br QOEt NaH, DMF Br 15-1 Br 15-2 PPA, PhMeI Ethyl Acrylate, Pd(OAc) 2
DMF
15-4 CO 2 Et S Me Ph L N Ph nBuLi, THF Pd(OH) 2
H
2 Me Bn 15-5 15-3
H
2 N ",,,_C02Et 15-6 WO 98/08840 WO 988840PCTIUS97/14912 163 SCHEME 15 (CONT'D)
*HCI
3-11 EDO, HOAT,
DMF
15-6 15-7 LiOH, EtOH,
H
2 0 15-8 WO 98/08840 PCTIUS9714912 164- 1-Bromo-3-(2.2-diethoxy-ethoxy)-benzene (15-2) To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0 °C was added a solution of 3-bromophenol 15-1 in DMF mL) over 40 min. After the addition was complete, the solution was stirred for an additional 30 min. The solution was then treated with neat bromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). The solution was heated at 100 oC for 8 h, cooled to room temperature, and extracted with Et20 (3 x 200 mL). The combined organic extracts were washed with 10% aq NaOH (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated to give 15-2 as a yellow oil.
TLC Rf 0.4 (10% ethyl acetate/hexanes).
1H NMR (300 MHz, CHC13) 8 7.19-7.05 3H), 6.85 1H), 4.81 (t, 1H, J=6.8 Hz), 3.99 2H, J=6.8 Hz), 3.71 4H), 1.22 6H, J=7.1 Hz) ppm.
6-Bromo-benzofuran (15-3) To a solution of the acetal 15-2 in toluene (200 mL) was added polyphosphoric acid (20 The biphasic mixture was heated to 100 °C and stirred at this temperature for 4 h. The mixture was cooled to room temperature, poured onto ice, and extracted with Et20 2 x 200 mL). The combined organic extracts were washed with saturated aq NaHCO3 and brine. The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (100% hexanes) to give the product 15-3 as a yellow oil.
TLC Rf 0.3 (100% hexanes).
1 H NMR (300 MHz, CHC13) 8 7.68 1H), 7.60 1H, J=2.1 Hz), 7.46 1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.1, 1.5 Hz), 6.75 (dd, 1H, J=7.1, 0.9 Hz) ppm.
3-Benzofuran-6-yl-acrylic acid ethyl ester (15-4) A mixture of the 6-bromobenzofuran 15-3 (1.74 g, 8.79 mmol), ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44 mmol), tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100 OC in a sealed WO 98/08840 PCT/US97/14912 165 tube for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted with Et20 (2 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the ester 15-4 as an off-white solid.
TLC Rf 0.3 (10% ethyl acetate/hexanes).
1 H NMR (300 MHz, CHC13) 8 7.78 1H, J=15.9 Hz), 7.68 1H, J=2.4 Hz), 7.66 1H), 7.59 1H, J=8.4 Hz), 7.43 (dd, 1H, J=9.0, Hz), 6.78 1H), 6.47 1H, J=15.9 Hz), 4.27 2H, J=7.2 Hz), 1.34 3H, J=7.2 Hz) ppm.
3-(S)-Benzofuran-6-yl-3-[benzyl-(1 (R)-phenyl-ethyl)-amino]-propionic acid ethyl ester (15-5) A solution of benzyl-o-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 0 oC was treated with n-BuLi (2.52 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0 °C for 30 min and then cooled to -78 OC. A solution of acrylate 15-4 (0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for min at -78 satd aq NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et20 (2 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the P-aminoester 15-5 as a yellow oil.
TLC Rf 0.8 (10% ethanol/dichloromethane).
1 H NMR (300 MHz, CHCI3) 5 7.58 3H), 7.41 2H), 7.22 (m, 9H), 7.59 1H), 4.58 1H), 4.05 1H), 3.91 2H, J=7.1 Hz), 3.72 2H), 2.62 2H), 1.21 3H, J=7.2 Hz), 1.03 3H, J=7.1 Hz) ppm.
3(S)-Amino-3-(2,3-dihydro-benzofuran-6-yl)-propionic acid ethyl ester (15-6) WO 98/08840 PCTIUS97/14912 166- A mixture of the dibenzylamine 15-5 (1.19 g, 2.78 mmol) in EtOH/H20/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (1.19 The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc, and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (10% ethyl acetate/dichloromethane) to give the ester 15-6 as a white solid.
TLC Rf 0.25 (10% ethanol/dichloromethane).
1 H NMR (300 MHz, CD30D) as the trifluoroacetate salt: 8 7.25 1H, J=8.1 Hz), 6.88 1H), 7.66 IH), 6.82 1H), 4.58 3H), 4.12 2H), 3.30 1H), 3.19 2H), 2.98 2H), 1.11 3H, J=7.2 Hz) ppm.
3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2- tetrahydro-[ 1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1 -yl acetvlamino)-propionic acid ethyl ester (15-7) A solution of the amine 15-6 (0.100 g, 0.425 mmol), acid 3-11 (0.155 g, 0.511 mmol), EDC (0.098 g, 0.511 mmol), NMM (0.103 g, 1.02 mmol), and HOAT (0.069 g, 0.511 mmol) in DMF 6 mL) was stirred at room temperature for 48 h. The solution was diluted with satd aq NaHCO3 (3 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography ethanol/dichloromethane) to give the ester 15-7 as an yellow oil.
TLC Rf 0.3 (10% ethanol/dichloromethane).
1 H NMR (300 MHz, CHC13) 8 7.12 2H), 6.78 IH), 6.65 1H), 6.39 1H), 5.36 4.99 (br s, 1H), 4.55 J=7.2 Hz, 2H), 4.11 2H), 3.91 2H), 3.39 2H), 3.19 2H), 2.79 2H), 2.70 2H), 2.51 1H), 2.28 2H), 1.85 3H), 1.18 3H) ppm.
3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2- tetrahydro-[ 1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl acetvlamino)-propionic acid (15-8) WO 98/08840 PCTIUS97/14912 167- A solution of the ester 15-7 (0.038 g, 0.073 mmol) in (4.5 mL/0.5 mL) was treated with LiOH (0.009 g, 0.365 mmol) and the homogeneous solution stirred at room temperature for 4 h. The solution was concentrated to a solid residue which was dissolved in H20 and purified by preparative HPLC (gradient conditions: 95:05 to 50:50 H20/MeCN with 0.1% TFA) to give the acid 15-8 as a white solid (as the bis-trifluoroacetate salt).
MS (LR, FAB) M +1 calcd 493, found 493.39.
1 H NMR (300 MHz, CHC13) 5 7.91 1H), 7.35 1H), 7.09 (m, 1H), 6.76 1H), 6.68 1H), 6.43 2H), 5.28 1H), 4.53 (m, 2H), 4.41 1H), 3.38 7H), 3.14 3H), 2.81 5H), 2.60 (m, 1H), 2.28 1H), 2.05 3H) ppm.
-WO 98/08840 PTU9/41 PCTIUS97/14912 168 SCHEME 16 DPPA, Et 3
N,
dioxane, benzylalcohoi H0 2
C
CbzNH
NH
0 16-2 16-1 NaH, BrCH 2 00 2 tBu
THF
HCI EtOAc CbzNH NI..~CO2 tBu 0 1- CbzNH N 2
H
o 16-4
N
IN 9 CbzNH yjN EDC, HOBT
DMF
16-5 WO 98/08840 WO 9808840PCTIUS97/14912 169 SCHEME 16 (cont.) 16-5
H
2 1O%Pd-C EtOH
IN,
H
2
N
0
N
H
16-6
H
N: N
CHO
14-3 NaB(OAc) 3
H
AcOH 4A seives
CH
2 CiC H 2
CI
C
kIK l''C0 2 Et 16-7 LIOH, H 2 0 MeOH y N -KC0 2
H
H
H
WO 98/08840 PCT/US97/14912 170- 3-Benzyloxycarbonylamino-6-methvl-2-pyridinone (16-2).
NH
CbzNH 0 DPPA (35.6 ml, 165 mmol) was added to a stirred solution of 2hydroxy-6-methylpyridine-3-carboxylic acid (16-1; Aldrich; 22.97 g, 165 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300 ml) and the resulting solution was heated to reflux. After 16 h more triethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 165 mmol) were added and the solution was refluxed for a further 24 h.
The reaction was concentrated in vacuo to remove most of the volatiles.
The residue was partitioned between methylene chloride (500 ml) and brine (500 ml), acidified to pH 1 with 1 M HCI (165 ml). The aqueous layer was extracted methylene chloride (two times) and the combined organic layers were washed with sodium hydrogen carbonate solution and brine, dried (Na2SO4) and evaporated in vacuo to a brown solid.
This was recrystallized from methanol, to give the title compound 16-2 as a tan solid: 1H NMR (300 MHz, CDC13) 6 2.29 3H, CH3), 5.20 2H, PhCH2), 6.06 J=7.6 Hz, pyridinone-5-H), 7.32-7.43 Ph), 7.67 (br s, 1H, CbzNH), 8.03 (br d, pyridinone-4-H).
2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin- -yl]acetic acid t-butyl ester CbzNH NC0 2 tBu
O
Sodium hydride (5.3 g, 0.22 mol) was added to a stirred slurry of 3benzyloxycarbonylamino-6-methyl-2-pyridinone (16-2; 53.2 g, 0.20 mol) in THF at 0°C. t-Butylbromoacetate (45 ml, 0.27 mol) was added WO 98/08840 PCT/US97/14912 171 to the resulting solution and a precipitate rapidly forms. The reaction was warmed to rt over Ih and after 2h the solvent was evaporated in vacuo and the residue was partitioned between 1:1 water/brine (200 ml) and 6:1 THF/methylene chloride (700 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo to a solid which was triturated with hexane to give the title compound 16-3 as a crystalline solid: 1H NMR (400 Mz, CDC13) 6 1.47 9H), 2.25 3H), 4.75 2 H), 5.19 2H), 6.09 J=7.8 Hz), 7.30-7.40 5H), 7.75 (br s, 1H), 7.94 (br d, 1H).
2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin- 1-yl]acetic acid (16-4).
CbzNH N CO 2
H
0 HC1 gas was bubbled through a stirred suspension of 2-[6-methyl-2-oxo- 3-(benzyloxycarbonylamino)-2H-pyridin- -yl]acetic acid t-butyl ester (16-3; 12.3 g, 33 mmol) in ethyl acetate (250 ml) at -15 0 C for 20 min.
The resulting solution was allowed to warm to room temperature and was then stirred there for 3 h. After purging with argon, the bulk of the solvent was rotavapped off and ether added to the residue. The solid which precipitated was filtered off and washed with ether. The title compound 16-4 was thus obtained as a white fluffy powder: 1H NMR 8 2.32 3 4.86 2 5.18 2 6.24 J 7.9 Hz, 1 7.31-7.41 6 7.94 (br s, 1 H).
{6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1 -yl) acetylamino)-3(S)-pyridin-3-vl-propionic acid ethyl ester (16-5).
WO 98/08840 PCT/US97/14912 172-
ON
N J C02Et CbzNH N N
CO
2 Et o
H
To a solution of the acid 2-4 (150 mg, 0.47 mmol) and the amine 1-9 (Rico et al; J. Org. Chem., 1993, 58, 7948; 139 mg, 0.52 mmol) in DMF (3 mL) was added HOBT (77 mg, 0.57 mmol) then Et3N (200 pL, 1.42 mmol). After 15 minutes, EDC (136 mg, 0.71 mmol) was added and the mixture was stirred for 16 hours. The solution was poured into EtOAc, washed with saturated NaHCO3 then brine, dried (MgSO4), and evaporated to give the title compound 16-5 as a white solid which was used as such in the next step. 1H NMR (CDC13) 8 1.14 (3H, 2.40 (3H, 2.8-2.9 (2H, 4.05 (2H, 4.78 (2H, 5.22 (2H, 5.4 (1H, 6.17 (1H, 7.22 (IH, 7.3-7.45 (4H, 7.59 (IH, 7.7-7.8 (2H, 8.0 (1H, 8.52 (2H, m).
6-methyl-2-oxo-3-amino-2H-pyridin-1 -yl} -acetylamino)-3(S)pyridin-3-vl-propionic acid ethyl ester (16-6).
N.N
H2 N NN C0 2 CH2CH3
HH
2
N
0
H
To a degassed solution of the pyridone 16-5 (243 mg; 0.49 mmol) in EtOH (20 mL) was added 10% Pd on carbon (25 mg) and this was then stirred under an atmosphere of hydrogen gas (balloon) for 3 hours.
The mixture was filtered through a pad of celite and the solvent removed to give the title compound (16-6) as a viscous oil which was used as such in the next step.
WO 98/08840 C/J9/41 PCT/US97/14912 173 (6-methyl-2-oxo-3 ,8-tetrahydro-[ 1 ,8]naphthyridin-2ylmethyl)-amino] -2H-pyridin- Il-yl I -acetylamino)-3(S )-pyridin-3 -yIp2rop~ionic acid ethyl ester (16-7).
NOD
H I N N 1 CO 2 Et N Q N H 0H To a solution of the amine 16-6 (155 mg, 0.433 mmol), the aldehyde 14-3 (70 mg, 0.433 mmol) in CH2ClCH2Cl was added crushed 4A seives, AcOH (20 pL) and then NaB(OAc)3H (184 mg, 0.866 mmol).
After stirring for 48 hours, the mixture was filtered through celite, poured into EtOAc and washed with saturated NaHCO3 then brine. The dried (MgSO4) solution was concentrated in vacuo to give a foam type solid. Column chromatography (5%MeOH in CHCl3) afforded the title compound 16-7 as a foam type solid.
Analysis calculated for C27H322N604-O.25CHC13 C, 61.24; H, 6.08; N, 15.73 found C, 61.33; H, 6.09; N, 15.85.
FAB mass spectrum. m/z 505.34 (M+H) {6-methyl-2-oxo-3 ,8-tetrahydro- [1 ,8]naphthyridin-2ylmnethyl)-amino] -2H-pyridin- Il-yl I -acetylamino)-3 (S )-pyridin-3 -yI p2rop~ionic acid bis trifluoroacetate (16-8).
H0 N NN,,CO2 IH H 0 WO 98/08840 PCT/US97/14912 -174- The ester 16-7 (120 mg, 0.238 mmol) was dissloved in H20 (1 mL) and THF (1 mL) and then IN LiOH (1 mL, 1 mmol) was added. After 2 hours, the mixture was purified by reverse phase HPLC (Waters PrepPak C18 column eluting with H20/acetonitrile gradient) to give, after lyophilization, the title compound 16-8 as a powder Analysis calculated for C25H28N604-2.5TFA*0.55H20 C, 46.70; H, 4.13; N, 10.89 found C, 46.70; H, 4.14; N, 11.04.
FAB mass spectrum. m/z 477.2 (M+H) WO 98/08840 WO 810840PCT/US97/14912 175 SCHEM~E17 0 Me 2 NCH(OMe) 2 pTSA Me MeN 0 0 2 N-1
NH
2 0 QNH HOAc 17-1 Z2 0 2 N
NH
NaH, THE BrCH 2 00 2 tBU K0 0 2 N
,A'
0 17-4 PtO 2
H
2 EtOH N,0
H
2 N ,k 0 17-5
H
N N CHO 14-3 NaBH(OAc) 3
CH
2
CICH
2
CI
WO 98/08840 WO 988840PCT/US97/14912 176 SCHEME 17 (cont.) 17Z-& LIGH, MeOH
H
2 0 N N C2 H 0 17-7
H
2 N OEt *HCI 0 17-8w F EDC, HOBT, DMF 0
F
H I N N~N NA.N 'K .C0 2 Et IH 0H 17-9 LiOH,
H
2 0 MeOH, THF 0
F
H 0 0 17-10 WO 98/08840 PCT/US97/14912 177 3-N.N-Dimethylaminoethenylcyclopropyl ketone (17-2).
Me Me -N 0 A mixture of cyclopropyl methyl ketone (5.88 ml, 59 mmol) and N,N-dimethylformaldehyde dimethyl acetal (7.83 ml, 59 mmol) was heated in the presence of a catalytic quantity of ptoluenesulfonic acid for 48 hours. The resulting crude sample of the title compound (17-2, a pale yellow oil) was used in subsequent reactions without further purification: 1 H NMR (CDC13) 8 0.74 2 1.00 2 1.75 1 3.48 3 3.50 3 5.20 1 7.55 1 H).
6-Cvclopropvl-3-nitro-2-(1 H)-pyridinone (17-3).
NH
0 2
N
0 A mixture of crude P-N,Ndimethylaminoethenylcyclopropyl ketone (17-2; 12 g, 86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100 ml) and piperidine (72 ml)] was stirred at room temperature overnight.
Following dilution with water (20 ml), the yellow precipitate was isolated via filtration and drying in vacuo to yield the title compound 17-3: 1H NMR (CDC13) 5 1.15 2 1.36 2 2.10 1 H), 6.02 (br d, J 8.0 Hz, 1 8.41 J 8.0 Hz, 1 H).
3-Nitro-6-cyclopropyl- 1 -(t-butyl-carboxymethvlene)-2-pyridinone (17- WO 98/08840 PCTIUS97/14912 178 N 0 0 2 N
O
0 Solid 6-cyclopropyl-3-nitro-2-(1H)-pyridinone (17-3; 1.4 g, 7.78 mmol) was added in small portions to a suspension of sodium hydride (260 mg, 10.8 mmol) in THF (30 ml) at room temperature.
After stirring the resulting solution for 20 min, tert-butylbromoacetate (4 ml, 27 mmol) was added. The mixture was stirred for an additional min. then heated at 55°C for 15 hrs. After cooling to room temperature the THF was evaporated in vacuo and ice carefully added to the residue to destoy any excess sodium hydride. The resulting miture was extracted with 2:1:1 ethyl acetate:ether:chloroform and the extracts dried over magnesium sulfate. Filtration and evaporation of the filtrate gave a yellow oil as a 3:1 mixture of N and O-alkylated products respectively. Flash column chromatography eluting with 1:1 hexane/ethyl acetate gave the title compound 17-4 as a yellow crystalline solid: 1 H NMR (CDC13) 8 0.94 2 1.18 2 1.49 9 H), 1.79 1 5.04 2 6.10 J 8.1 Hz, 1 8.33 J 8.1 Hz, 1 H).
3-Amino-6-cyclopropyl- 1 -(t-butyl-carboxymethvlene)-2-pyridinone (17-5)
H
2 N O 0 A mixture of 3-nitro-6-cyclopropyl- -(t-butyl-methylenecarboxy)-2-pyridinone (17-4; 760 mg, 2.58 mmol) and platinum oxide (250 mg) in ethanol (30 ml) was stirred at 0° C under an atmosphere of WO 98/08840 PCTIS97/14912 179hydrogen for 3 hours. Following removal of most of the catalyst by filtration through a bed of Celite, the filtrate was concentrated and the residue purified by flash column chromatography eluting with 2:1 hexane/ethyl acetate. This yielded the title product 17-5 as a viscous orange gum: 1 H NMR (CDC13) 8 0.67 2 0.89 2 1.49 (s, 9 1.63 1 4.07 (br s, 2 4.99 2 5.91 (dd, J 1.2 and 7.4 Hz, 1 6.47 J 7.4 Hz, 1 H).
6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2ylmethyl) -amino]-2H-pyridin- -y l-acetic acid tert-butyl ester (17-6) H 0 N NN O
N
Following the procedure described for the synthesis of 16-7, the amine 17-5 was coupled with 14-3 to yield the title compound 17-6 as an oil.
Rf (silica gel; 5%MeOH in CHC13) 0.39 {6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[ 1,8]naphthyridin-2ylmethyl) -aminol-2H-pyridin- 1-y l-acetic acid (17-7).
H02
H
N
H
Following the procedure described for the preparation of 16-8, the ester 17-6 was hydrolysed to give the title compound 17-7. IH NMR 6 0.66 2 0.9 2 1.78 1 1.9 2H), WO 98/08840 WO 9808840PCTIUS97/14912 -180- 2.75 (in, 2H), 3.4 (in, 2H), 4.6 (br s, 2 6.02 I1H), 6.19 I H), 8 (in, 1 7.27 (mn, I1H).
Ethyl 3-amino-3(S)-(3-fluorophenyl )propionate hydrochloride (17-8).
-HCI
The title compound was prepared starting from 3-fluorobenzaldehyde (Aldrich) by conversion to ethyl 3-fluorocinnainate and employing the asymmetric addition/hydrogenolysis methodology described by Rico et al; J. Org. Chem., 1993, 58, 7948.
IH NMR (CD3OD) 8 1.21 3H), 3.03 (dd, 1H), 3.13 (dd, 1H), 4.15 2H), 4.77 1H), 7.19 (in, 1H), 7.3 (mn, 2H), 7.5 (in, 1H).
3-(2-1t6-Cyclopropyl-2-oxo-3-[(5 ,6,7 ,8-tetrahydro-[ 1 ,8]naphthyridin-2ylmnethyl)-amino]-2H-pyridin- 1 -yl I -acetylamino)-3(S)-(3-fluorophenyl)propionic acid ethyl ester (17-9).
Following the procedure described for the preparation of 16-5, the acid 17-7 was coupled with the amine 17-8 to yield the title compound 17-9.
Analysis calculated for C30H34N504 Fl -0.25H20 C, 65.26; H, 6.30; N, 12.69 found C, 65.20; H, 6.04; N, 13.00.
WO 98/08840 WO98/0840PCTIUS97/14912 181 FAB mass spectrum. m/z 548.12 (M+H) 3 6 -Cyclopropyl-2-oxo-3-[(5 ,6 ,7,8-tetrahydro-[ 1 ,8]naphthyridin-2ylmethyl)-amino] -2H-pyridin- Il-yI -acetylamino)-3(S -fluorophenyl)propionic acid ditrifluoroacetate (17-10).
0
C
H
N N N I J1C02 IH 0H Following the procedure described for the preparation of 16-8, the ester 17-9 was hydrolysed to give the title compound 17-10.
Analysis calculated for C28H30N504 Fl -2.1 5TFA.0.5H20 C, 55.16; H, 4.91; N, 10.62 found C, 55.19; H, 4.91; N, 10.89.
FAB mass spectrum. m/z 520.05 (M+H) 3 6 -Cyclopropyl-2-'Oxo-3 ,8-tetrahydro-[ 1,8]naphthyridin-2yhnethyl)-amnino]-2H-pyridin- l -yl I -acetylamino)-3(S)-(3-pyridyl)prop~ionic acid ditrifluoroacetate (17-11
NN
I
0H Following the procedures described for Scheme 16, the acid 17-7 was coupled with the amine 1-9 followed by saponification of the ester to afford the title compound 17-11.
Analysis calculated for C27H30N6O402.5TFA-O.6H20 WO 98/08840 WO 9808840PCT/US97/14912 182- C, 48.13; H, 4.25; N, 10.53 found C, 48.11; H, 4.23; N, 10.64.
FAB mass spectrum. mlz 503.25 (M+H) I6-Cyclopropyl-2-oxo-3- ,8-tetrahydro-[ 1 ,8]naphthyridin-2ylmethyl) -amino] -2H-pyridin- l -yl I -acetylamnino)-3 (S )-(alkynyl)p2rop~ionic acid ethyl ester (17-12).
H
00 Following the procedures described for Scheme 16, the acid 17-7 was coupled with 3-amino-3(S)-(alkynyl)-propionic acid ethyl ester 2-9 (Zablokie et al, J. Med. Chem., 1995, 38, 2378) to afford the title compound 17-12.
Analysis calculated for C26H3 1 N504-O.35H20 C, 64.53; H, 6.60; N, 14.47 found C, 64.52; H, 6.71; N, 14.54.
FAB mass spectrum. mlz 478.35 (M+H) (6-Cyclopropyl-2-oxo-3- ,8-tetrahydro-[ 1,8]naphthyridmn-2ylmethyl)-amino] -2H-pyridin- l-yl I-acetylamino)-3 (S )-(alkynyl)p2ropionic acid (17-13).
H
0
H
N N IH 0H WO 98/08840 PCTAS97/14912 183 Following the procedure described for the preparation of 16-8, the ester 17-12 was hydrolysed to give the title compound 17-13.
FAB mass spectrum. m/z 450.23 (M+H) WO 98/08840 WO 8/0840PCTIUS97/14912 184 SCH1EME18
H
2 N CO 2 Bn 18-1
CH
3 0HO TMSCN NCY, (COCd) 2 HNI,,CO 2 Bn Q6HA2
CI
N -Y ClIjtNC 2 Bn 0 4-MeOPhCH 2 2 EtOAc MeO ylCOBn *0 RaNi, NaOH MeO Nl N 0 N-N OH H 0 LiOH, H 2 0 MeOH, THF MeO N0 N N)KOH H 0 18-5
TFA
18-7 WO 98/08840 WO 9808840PCTIUS97/14912 185 SCHEME 18 (cont.)
H
2
N.
-HCI
0
H
2
N
"NF
N CO 2
E
H
18-8 .18-7 17-8 Nz EDC, HOBT, DMF
H
N N CHO NaBH(OAC) 3
CH
2
CICH
2
CI
2. LIOH, H 2 0 THF, MeOH N N 1
NF
N N N-'yN,,k CO2H H H 0
H
WO 98/08840 PCT/US97/14912 186- Benzvl-N-( 1-cyanoethyl)glycine hydrochloride (18-2).
NC HN CO 2 Bn TMSCN (18.8 mL, 141 mmol) was added cautiosly to a stirred solution of benzylglycine free base (23.3 g 141 mmol from the HCI salt by partition between EtOAc and brine basified with saturated Na2CO3 solution) and acetaldehyde (7.88 mL, 141 mmol) in CH2C12 (50 mL).
After 4 h the volatiles were removed in vacuo and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil. The oil was redissolved in EtOAc and 9.9 M HCI in EtOH (15.25 mL, 151 mmol) was added to give a crystalline precipitate which was isolated by filtration, washing with EtOAc and Et20 to give the title compound (18-2): 1H NMR (CD30D) 8 1.70 3H), 4.16 1H), 4.21 1H), 4.64 (q, 1H), 5.31 2H), 7.35-7.44 1-Benzvloxycarbonvlmethyl-3.5-dichloro-6-methylpyrazinone (18-3).
CI
C1, N
CO
2 Bn
O
A stirred mixture of oxalyl chloride (40.4 mL, 463 mmol) and 18-2 (29.51 g, 116 mmol) in 1,2-dichlorobenzene (110 mL) was heated to 100 0 C for 15 h. The volatiles were removed in vacuo and the residue was purified by chromatography (silica gel; hexanes followed by in hexanes) to give a solid which was heated in EtOAC/hexanes 2:5 (140 mL), cooled and collected by filtration to give the title compound 18-3 as a pale green solid: WO 98/08840 WO 9808840PCT/US97/14912 187 IH NMR (CDCl3) 5 2.35 3H), 4.88 2H), 5.24 2H1), 7.38 (in, 3 4 -Methoxybenzylamino)-5-chloro..&methyl-. 1 benzyloxvcarbonylmethyl -p2yrazinone (18-4).
MeO N y N' N,..C0,Bn H 0 A solution of the pyrazinone 18-3 (5 g, 15.3 minol) and 4 methoxybenzylaxnine (6.0 mL, 45.9 minol) in EtOAc (60 mE) was heated at 80'C for 2 hi. The solution was cooled and filtered. The filtrate was concentrated in vacuo, the residue swished with MeOH and filtered to afford the title compound as a solid: I H NMR (CDC13) 8 2.23 3H), 3.82 311), 4.5 211), 4.81 2H), 5.22 2H), 6.25 1H1), 6.85 (mn, 2H), 7.27 (in, 2H), 7.38 (in, 511).
3 -(4-Methoxybenzylamino)-s -chloro-6-inethyl-l1-carboxyinethyl p2yrazinone (18-5).
MeO ~NN- 0
N
0 A solution of the benzyl ester 18-4 1.06 g, 2.48 mmol) in toluene mL) was degassed with argon and then 150 mng 10% palladium on carbon was added. The mixture was stirred under an atmosphere of WO 98/08840 PCT/US97/14912 188hydrogen gas for 16 h. The solution was filtered through celite and the solvent evaporated to give the title compound 18-5 as a white solid: IH NMR (CD30D) 8 2.25 3H), 3.78 3H), 4.45 2H), 4.81 (s, 2H), 4.90 2H), 6.85 2H), 7.28 2H).
3-(4-Methoxybenzylamino)- 6-methyl-i -carboxymethyl pyrazinone (18-6).
MeO
N
N YN H H
O
The acid 1 8-5 (810 mg) was dissolved in 40 mL 1 N NaOH and 40 mL MeOH at room temperature and was treated with Raney nickel suspension A second charge of Raney nickel g) and 1 N NaOH (20 mL) was added after 3 h. After 6 h, the suspension was filtered through celite washing with water and MeOH. The volatiles were removed in vacuo and the residue then taken up I N HCI mL).
Saturated NaHCO3 solution was added until pH~-7-8 and the solution was extracted exhaustively with EtOAc/THF. After drying (MgS04), the solvent was removed to give the title compound 18-6 as a solid which was used as such: 1 H NMR (CD30D) 8 2.16 3H), 3.76 3H), 4.46 2H), 4.64 (s, 2H), 4.86 2H), 6.65 1H), 6.85 2H), 7.25 2H).
3-Amino-6-methvl-l-carboxvmethvlpvrazinone (18-7).
WO 98/08840 WO 9808840PCTIUS97/14912 189 The pyrazinone 18-6 (900 m g) was heated at reflux in tnifluoroacetic acid (20 mL) for 7 h. The volatiles were removed in vacuc and the residue was azeotroped with CH2C12, then EtOAc then MeOH. MeGH was added to the residue and the solution filtered to remove impurities.
Removal of the methanol then afforded the title compound 18-7 which was used as such: I H NMR (CD3OD) 8 2.22 3H), 4.82 2H), 6.58 I1H).
3 -(3-Fluorophenyl)-3-(2- f 6 -methyl-2-oxo-3 -amino] -2H-pyrazin- Il-yl}acetylamino)p2ropionic acid ethyl ester 01 8-8).
F
I NJN,
C
2 Et
H
2
NN
Ao
H
Following the procedure described for the preparation of 16-6, the acid .18-7 was coupled with the amine 17-8 to yield the title compound 18-8.
1H NMR (CDCI3) 5 1.15 3H), 2.23 3H), 2.78 (dd, 1H), 2.84 (dd, 1H), 4.05 2H), 4.68 (ABq, 2H), 5.30 (br s, 2H), 5.35 (in, 1H), 6.68 1H), 6.9-7.1 (in, 3H), 7.27 (mn, 1H), 7.57 2H).
3 3 -Fluorophenyl)-3-(2- 6-methyl-2-oxo-3 ,6,7,8-tetrahydro- 1 ,]naphthyridin-2.ylmethyly..aminoy.2H..pyrazin.1 .yl I -acetylamino)propionic acid ditrifluoroacetate (1 8-9).
H
N NIN,'AC 2
H
N N-r N IH 0H WO 98/08840 PCT/US97/14912 -190- Following the procedure described for the synthesis of 16-9, the amine 18-8 was coupled with 14-3 and the product hydrolyzed to yield the title compound 18-9.
Analysis calculated for C25H27N604F-2.25TFA-0.85H20 C, 46.23; H, 4.07; N, 10.97 found C, 46.22; H, 4.00; N, 11.12.
FAB mass spectrum. m/z 495.26 (M+H) WO 98/08840 PTU9/41 PCT[US97/14912 191 SCHEME 19 0 Lii (cat.) 19-- 0 r 'OH
HO
TsOH (cat.)
H
2 Pd/C 0 CI JO'Bu NEt 3
H
H
2 N- NCH 3
NH
I-j 1 Cl-4 19-5 0 Br,,A OEt NaN(SiMe 3 2 TsOH (cat.) acetone 19-6 0 QEt
N
0 0 OH 3 0 0 19-7 WO 98/08840 WO 9808840PCTIUS97/14912 192 SCHEME 19 ContXd 0 OEt
I
0 -N NH R 1-4 0 19-7 proline (cat.) M I 0Et 19-8
IH
2 Pd/C N 0 OEt 19-9 6N HCI 0
CH,
19-10 WO 98/08840 WO 8/0840PCTIUS97/14912 193 SCHEME 19 (Cont'd) EDO, HOBT
NMM
*HCI
2-9 ,OEt 19-z11 I NaOH 19-12 -WO 98/08840 PCT/US97/14912 194 The test procedures employed to measure avp3 binding and the bone resorption inhibiting activity of the compounds of the present invention are described below.
BONE RESORPTION-PIT ASSAY When osteoclasts engage in bone resorption, they will literally cause the formation of pits in the surface of bone that they are acting upon. Therefore, when testing compounds for their ability to inhibit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present.
Consecutive 200 micron thick cross sections from a six mm cylinder of bovine femur diaphysis were cut with a low speed diamond saw (Isomet, Beuler, Ltd., Lake Bluff, II). Bone slices were pooled, placed in a 10% ethanol solution and refrigerated until further use.
Prior to experimentation, bone slices were ultrasonicated twice, 20 minutes each in H20. Cleaned slices were placed in 96 well plates such that two control lanes and one lane for each drug dosage are available. Each lane represents either triplicate or quadruplicate cultures. The bone slices in 96 well plates were sterilized by UV irradiation. Prior to incubation with osteoclasts, the bone slices were hydrated by the addition of 0.1 ml Medium 199, pH 6.9 containing fetal bovine serum and 1% penicillin/streptomycin.
Osteoclasts were isolated from the long bones of 1 to 3 day old rat pups (Sprague-Dawley) by modifications of Chambers et al., (L Cell. Science, 66:383-399). The resulting suspension (0.75 ml/bone) was gently triturated 90-120 times using a wide bore transfer pipet.
The cellular population was separated from bone fragments by a cell strainer with a 100 micron nylon mesh. 100 Rl of the cell suspension was placed onto each bone slice. Test compounds were then added at the desired experimental concentrations.
Bone slices exposed to osteoclasts for 20-24 hrs were processed for staining. Tissue culture media was removed from each bone slice. Each well was washed with 200 gl of H20, and the bone slices were then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M WO 98/08840 PCT/US97/14912 195 cacodylate, pH 7.4. After fixation, any remaining cellular debris was removed by 2 min. ultrasonication in the presence of 0.25 M followed by 2 X 15 min ultrasonication in H20. The bone slices were immediately stained for 6-8 min with filtered 1 toluidine blue and 1 borax.
After the bone slices have dried, resorption pits were counted in test and control slices. Resorption pits were viewed in a Microphot Fx (Nikon) fluorescence microscope using a polarizing Nikon IGS filter cube. Test dosage results were compared with controls and resulting IC50 values were determined for each compound tested.
The appropriateness of extrapolating data from this assay to utility and use in mammalian (including human) disease states is supported by the teaching found in Sato, et al., Journal of Bone and Mineral Research, Vol. 5, No. 1, 1990. That article teaches that certain bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay described above to confirm a correlation between their known utility and positive performance in the assay.
EIB ASSAY Duong et al., J. Bone Miner. Res., 8:S 378, describe a system for expressing the human integrin cavp3. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies against the integrin, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption.
Reaction Mixture: 1. 175 pl TBS buffer (50 mM Tris-HCI pH 7.2, 150 mM NaC1, 1% BSA, 1 mM CaCl2, 1 mM MgCl2).
WO 98/08840 PCT/US97/14912 196- 2. 25 l cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 gl).
3. 1 2 5 I-echistatin (25 L1/50,000 cpm) (see EP 382 451).
4. 25 gLl buffer (total binding) or unlabeled echistatin (nonspecific binding).
The reaction mixture was then incubated for 1 h at room temp. The unbound and the bound av33 were separated by filtration using a Skatron Cell Harvester. The filters (prewet in 1.5% polyethyleneimine for 10 mins) were then washed with the wash buffer mM Tris HC1, ImM CaCl2/MgC12, pH The filter was then counted in a gamma counter.
SPA ASSAY
MATERIALS:
1. Wheatgerm agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem 4. NaCI: Fisher CaCI2: Fisher 6. MgCl2: SIGMA 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 8. Optiplate: PACKARD 9. Compound 8-10 (specific activity 500-1000 Ci/mmole) test compound 11. Purified integrin receptor: vvP3 was purified from 293 cells overexpressing cav33 (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 NaC1, 1 mM Ca 2 +/Mg 2 0.5 mM PMSF WO 98/08840 PCTIUS97/14912 197 13. 50 mM octylglucoside in binding buffer: 50-OG buffer
PROCEDURE:
1. Pretreatment of SPA beads: 500 mg of lyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer.
2. Preparation of SPA beads and receptor mixture In each assay tube, 2.5 pl (40 mg/ml) of pretreated beads were suspended in 97.5 pl of binding buffer and 20 gLl of buffer. 5 [l (~30 ng/pl) of purified receptor was added to the beads in suspension with stirring at room temperature for minutes. The mixture was then centrifuged at 2,500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4°C. The pellets were then resuspended in 50 tpl of binding buffer and ptl of 50-OG buffer.
3. Reaction The following were sequentially added into Optiplate in corresponding wells: Receptor/beads mixture (75 1l) (ii) 25 pl of each of the following: compound to be tested, binding buffer for total binding or 8-8 for non-specific binding (final concentration 1 pgM) (iii) 8-10 in binding buffer (25 p1l, final concentration 40 pM) (iv) Binding buffer (125 .1) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4 0
C
4. Plates were counted using PACKARD TOPCOUNT inhibition was calculated as follows: A total counts WO 98/08840 PCTIVS97/14912 198- B nonspecific counts C sample counts inhibition x 100 OCFORM ASSAY Osteoblast-like cells (1.8 cells), originally derived from mouse calvaria, were plated in CORNING 24 well tissue culture plates in oa MEM medium containing ribo- and deoxyribonucleosides, fetal bovine serum and penicillin-streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows: Mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syringe with a 27.5 gauge needle.
The marrow was suspended by pipetting up and down. The suspension was passed through >100 grm nylon cell strainer. The resulting suspension was centrifuged at 350 x g for seven minutes. The pellet was resuspended, and a sample was diluted in 2% acetic acid to lyse the red cells. The remaining cells were counted in a hemacytometer. The cells were pelleted and resuspended at 1 x 106 cells/mL. 50 kL was added to each well of 1.8 cells to yield 50,000 cells/well and 1,25-dihydroxyvitamin D3(D3) was added to each well to a final concentration of nM. The cultures were incubated at 37°C in a humidified, 5% C02 atmosphere. After 48 h, the medium was changed. 72 h after the addition of bone marrow, test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with fresh medium containing D3. After an additional 48 h the medium was removed, cells were fixed with 10% formaldehyde in phosphate buffered saline for 10 minutes at room temperature, followed by a 1-2 minute treatment with ethanol:acetone and air dried. The cells were then stained for tartrate resistant acid phosphatase as follows: The cells were stained for 10-15 minutes at room temperature with 50 mM acetate buffer, pH 5.0 containing 30 mM WO 98/08840 PCT/US97/14912 -199sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dried. The number of multinucleated, positive staining cells were counted in each well.
ATTACHMENT ASSAY Duong et al., J. Bone Miner. Res., 11:S 290, describe a system for expressing the human Materials: 1. Media and solutions used in this assay are purchased from BRL/Gibco, except BSA and the chemicals are from Sigma.
2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid free BSA and 2 mM CaCl2.
3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl-Nacetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.
Methods: 1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4 OC with human vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH using 100 pl/well. Plates were then washed 2X with DPBS and blocked with 2% BSA in DPBS for 2h at room temperature. After additional washes (2X) with DPBS, plates were used for cell attachment assay.
2. 293 (alpha v beta 5) cells were grown in MEM media in presence of 10% fetal calf serum to 90% confluence. Cells were then lifted from dishes with 1X Trypsin/EDTA and washed 3X with serum free MEM. Cells were resuspended in attachment medium (3 X 105 cells/ml).
3. Test compounds were prepared as a series of dilutions at 2X concentrations and added as 50 pl/well. Cell suspension was WO 98/08840 PCTIUS97/14912 -200then added as 50 ml/well. Plates were incubated at 37 °C with C02 for 1 hour to allow attachment.
4. Non-adherent cells were removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase substrate solution (100 [l/well), overnight at room temperature in the dark. To quantitate cell numbers, standard curve of glucosaminidase activity was determined for each experiment by adding samples of cell suspension directly to wells containing the enzyme substrate solution.
5. The next day, the reaction was developed by addition of 185 pl/well of gylcine/EDTA solution and reading absorbance at 405 nm using a Molecular Devices V-Max plate reader.
Average test absorbance values (4 wells per test samples) were calculated. Then, the number of attached cells at each drug concentration was quantitated versus the standard curve of cells using the Softmax program.
EXAMPLE OF A PHARMACEUTICAL FORMULATION As a specific embodiment of an oral composition, 100 mg of compound 3-13 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
Representative compounds of the present invention were tested and found to bind to human avP3 integrin. These compounds were found to have IC50 values in the range of 0.1 to 100 nM in the SPA assay.
Representative compounds of the present invention were tested and found to inhibit 50% the attachment of av35 expressing cells to plates coated with vitronectin at concentrations of 1 kM.
While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the WO 98/08840 PCTfUS97/14912 -201 invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims (35)

1. A method of eliciting a vitronectin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula 0 8 R R 9 OR R 1 wherein X is selected from R 1 NR 2 N R II NR iR 2 -NR 1 C-NR'R 2 a 5- or 6-membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the 5- or 6-membered ring system is either unsubstituted or substituted with one or more groups chosen from R 1 R 2 R 15 or R1 6 a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring ""system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with one or more groups chosen from R 1 R 2 R 1 or R16; 'Y-is selected from WO 98/08840 PTU9141 PCTIUS97/14912 203 R 3 0 0 0 -(CH 2 )-C-N-(CH 2 (C H 2 )f-N C H 2 )W- -(CH2S(02--(CHOW -(CH2)FN S(O) 2 -(H 2 )Wn -(CH 2 )jS(O)q-(CH 2 )m (C O-(CH 2 or -(CH 2 Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, 0 and S, and wherein the ring system is either unsubstituted or substituted with one or more groups independently selected from R 4 R 5 R 6 and R 7 provided that Z is not a 6-membered monocyclic aromatic ring system, an isoxazoline ring or an isoxazole ring; R 1, R 2 R 4 R 5 R 1 3 R 1 4 R 15 and R 1 6 are each independently selected from hydrogen, halogen, Ci -10 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-.8 cycloheteroalkyl C1-6 alkyl, aryl, aryl Ci -8 alkyl, amino, amino C 1-8 alkyl, C 1-3 acylamino, C 1-3 acylamnino C 1-8 alkyl, (Ci -6 alkyl)qamino, (CI -6 alkyl)qamino C1-8 alkyl, Ci1 -4 alkoxy, Ci1 -4 alkoxy Ci1 -6 alkyl, hydroxycarbonyl, hydroxycarbonyl. Ci1 -6 alkyl, C 1 -3 alkoxycarbonyl, Ci1 -3 alkoxycarbonyl Ci1 -6 alkyl, hydroxycarbonyl- C 1-6 alkyloxy, hydroxy, hydroxy C 1-6 alkyl, C 1-6 alkyloxy- Ci1 -6 alkyl, nitro, cyano, trifluorornethyl, trifluoromethoxy, trifluoroethoxy, CI-g alkyl-S(0)q, (CI-8 alkyl)qaminocarbonyl, WO 98/08840 WO 9808840PCTIUS97/14912 -204- Ci1 -8 alkyloxycarbonylamino, (Cl1-8 alkyl)qaminocarbonyloxy, oxo, (aryl C 1.-8 alkyl)qamino, (aryl)qamino, aryl C 1-8 alkylsifonylamino or C 1-8 alkylsulfonylamino; R 3 is selected from hydrogen, aryl, aryl-(CH2)p-, hydroxyl1, Ci1-5 alkoxy, amninocarbonyl, C3-8 cyclojalkyl, amino C 1-6 alkyl, (aryl)qaminocarbonyl, (aryl CI-5 alkYl)qaminocarbonyl, hydroxycarbonyl CI -6 alkyl, C1-8 alkyl, aryl Ci -6 alkyl, (C 1 -6 alkyl)qamino Ci1 -6 alkyl, (aryl C 1 -6 alkYl)qamino Ci1 -6 alikyl, Ci1 -8 alkylsulfonyl, Ci1 -8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci -8 alkoxycarbonyl, CI -8 alkylcarbonyl, arylcarbonyl, aryl CI -6 alkylcarbonyl, (C 1-8 alkyl)qaminocarbonyl, amino sulfonyl, C 1 -8 alkylaminosulfonyl, (aryl)qaminosulfonylamino, (aryl Cl-g alkyl)qamninosulfonyl, C 1 -6 alkylsulfonyl, arylsulfonyl, WO 98/08840 PTU9/41 PCT/US97/14912 205 aryl Ci1 -6 alkylsulfonyl, aryl C 1-6 alkylcarbonyl, C 1 -6 alkyithiocarbonyl, aryithiocarbonyl, or aryl Ci -6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with RI 3 and R1 4 R 6 R 7 R 8 R 9 R 10 and R I are each independently selected from hydrogen, aryl, aryl-(CH2)p-, aryl-(CH2)n-O-(CH2)rn-, aryl-(CH2)n-S(O)q-(CH2)m-, aryl-(CH2)n-C(O)-(CH2)m-, aryl-(CH2)n-C(O)-N(R 3 aryl-(CH2)n,-N(R 3 aryl-(CH2)n-N(R 3 halogen, hydroxyl, Ci1 -8 alkylcarbonylamino, aryl CI-5 alkoxy, alkoxycarbonyl, (Ci1 -8 alkyl)qaminocarbonyl, Ci1 -6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (Ci1 -6 alkyl)qamino, ammno Cl1-6 alkyl, arylaminocarbonyl, aryl alkylaminocarbonyl, aminocarbonyl, amninocarbonyl Cl-6 alkyl, hydroxycarbonyl, WO 98/08840 WO 988840PCTIUS97/14912 206 hydroxycarbonyl C 1-6 alkyl, Ci1 -8 alkyl, either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, C 1-5 alkylcarbonylamino, aryl Ci1-5 alkoxy, Ci1 -5 alkoxycarbonyl, aminocarbonyl, (C 1 -5 alkyl)qamino- carbonyl, Ci1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (Ci -3 alkyl)qamino, amino CI -3 alkyl, (aryl)qaminocarbonyl, (aryl C.1-5 alkyl)qaminocarbonyl, aminocarbonyl, aminocarbonyl Ci1 -4 alkyl, hydroxycarbonyl or hydroxycarbonyl CI -5 alkyl, CH=-C-(CH2)s-, CI -6 alkyI-C=-C-(CH2)s-, C3-7 cycloalkyl-C=-C-(CH2)s-, aryl-C=EC-(CH2)s-, CI-6 alkylary1-C=-C-(CH2)s-, CH2=CH-(CH2)s-, Ci -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, C 1 6 alkylaryl-CH=CH-(CH2)s-, Ci1 -6 alkyl-S02-(CH2)s-, Ci1 -6 alkylaryl-S02-(CH2)s-, C 1-6 alkoxy, aryl C1-6 alkoxy, aryl C 1.6 alkyl, (C 1-6 alkyl)qamino CI1-6 alkyl, (aryl)qamino, (aryi)qamino C1-6 alkyl, (aryl C1-6 alkyl)qamino, (aryl Ci1 -6 alkyl)qamino Ci1 -6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1 -6 alkYl)qaminocarbonyloxy, Ci1 -8 alkylsulfonylammno, -WO 98/08840 PTU9/41 PCTIUS97/14912 207 arylsulfonylamino, C 1 -8 alkylsulfonylamino Ci1 -6 alkyl, arylsulfonylamino Ci -6 alkyl, aryl CI-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino CI-6 alkyl, Ci -8 alkoxycarbonylamino, Ci -8 alkoxycarbonylamino CI -8 alkyl, aryloxycarbonylamino CI -8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl Ci-g alkoxycarbonylamino Ci .g alkyl, Ci1 -8 alkylcarbonylamino, C1 -8 alkylcarbonylamino Ci1 -6 alkyl, arylcarbonylamino C 1 -6 alkyl, aryl Ci -6 alkylcarbonylamino, aryl Ci -6 alkylcarbonylamino C 1 -6 alkyl, aminocarbonylamino C1-6 alkyl, (Ci1 -8 alkyl)qaminocarbonylamino, (Ci-8. alkYl)qaminocarbonylamino C1-6 alkyl, (aryl)qaminocarbonylamino Ci -6 alkyl, (aryl Ci -8 alkYl)qaminocarbonylamino, (aryl C 1.-8 alkyl)qaminocarbonylamino C1 -6 a aminosulfonylamino Ci1 -6 alkyl, (C 1-8 alkyl)qaminosulfonylamino, (CI -8 alkyl)qaminosulfonylamino Ci -6 alkyl, (aryl)qaminosulfonylamino Ci -6 alkyl, (aryl Ci1 -8 alkyl)qaininosulfonylamino, (aryl Ci1 -8 alkyl)qaminosulfonylarnino Ci1 -6 al Ci1 -6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C 1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl Ci -6 alkylsulfonyl CI -6 alkyl, Ci -6 alkylcarbonyl, Cl-6 alkylcarbonyl C1-6 alkyl, Ikyl, kyl, WO 98/08840 PCTfUS97/14912 -208- arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino CI-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C -6 alkyl, (C1-8 alkyl)qaminocarbonyl Cl-6 alkyl, (aryl)qaminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)qaminocarbonyl, or (aryl C1-8 alkyl)qaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and R1 4 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R 10 and R 11 are attached is itself attached to no more than one heteroatom; R 1 2 is selected from hydrogen, Cl-8 alkyl, aryl, aryl C1-8 alkyl, C1-8 alkylcarbonyloxy C1-4 alkyl, aryl C1-8 alkylcarbonyloxy Ci-4 alkyl, C1-8 alkylaminocarbonylmethylene, or Cl-8 dialkylaminocarbonylmethylene; m, s and t are each independently an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; WO 98/08840 PCT/US97/14912 -209- and the pharmaceutically acceptable salts thereof.
2. The method of Claim 1, wherein X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R 1 and R 2 and Z is selected from 4H N H WO 98/08840 PTU9/41 PCTIUS97/14912 -210- Ny 0 R 7 R 4 ,or R 6 and the pharmaceutically acceptable salts thereof.
3. The method of Claim 2, wherein Z is selected from 0 0 0 WO 98/08840 PCTIUS97/4912 -2111- NJ vq 0 0 0 0 0 H 0 NH N 0tL Y N 0 0"- 0 Y-X 0 K or t,NY l 0 WO 98/08840 PTU9141 PCT/US97/14912 212 and the pharmaceutically acceptable salts thereof.
4. The method of Claimn 3 wherein the compound has the formula R 8 0 1 C2R1 wherein X is selected from R1R R 1 ONN N~ NAS or C'~N r H H H Y is selected from -(CH2)r- or -(CH2)m-NR 3 -(CH2)t-; R 3 is selected from hydrogen, aryl-(CH2)p-, alkoxycarbonyl, C3-8 cycloalkyl, (aryl)qaminocarbonyl, (aryl CI-5. alkyl)qaminocarbonyl, C1 -8 alkyl, aryl C1-6 alkyl, Ci 1 alkylsulfonyl, arylsulfonyl, aryl Ci -6 alkylsulfonyl, Ci1 -8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, Ci1 -8 alkylcarbonyl, arylcarbonyl, aryl Ci -6 alkylcarbonyl, (Ci1 -8 alkyl)qaminocarbonyl, WO 98/08840 PTU9/41 PCTfUS97/14912 213 Ci1 -6 alkylsulfonyl, or aryl C 1-6 alkylcarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 13 and R 1 4 R 4 is selected from hydrogen, CI-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl CI-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl or aryl Cp-g alkyl, R 8 is selected from hydrogen, aryl, aryl-(CH2)p-, CH=-C-(CH2)s-, Ci1 -6 alkyl-C=-C-(CH2)s-, C3-7 cycloalkyl-C=-C-(CH2)s-, aryl-C=-C-(CH2)s-, CI -6 alkylaryl-C=-C-(CH2)s-, CH2=CH-(CH2)s-, C 1 -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, Ci1 -6 alkylaryl-CH=CH-(CH2)s-, C 1-6 alkyl-S02-(CH2)s-, C1-6 alkylaryl-S02-(CH2)s-; and r is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof. The method of Claim 4 wherein the compound has the formula .WO 98/08840 PTU9/41 PCTIVS97/14912 -214- 0 11 Z- CH 2 CNH R 8 wherein Z is selected from 0 00 rh' 0 N N-i -~0 0 R 8 is selected from hydrogen, 0 F N C 0IC 0 I N 0 N H indolyl-(CH2)p-, CHF-C-(CH2)s-, C.1-6 alkyl-C=-C-(CH2)s-, C3-7 cycloalkyl-C=C-(CH2)s-, aryl-C=-C-(CH2)s-, WO 98/08840 PTU9/41 PCT/US97/14912 215 CI -6 alkylary1-C=-C-(CH2)s-, CH2=CH-(CH2)s-, CI -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, Ci1 -6 alkylaryl-CH=CH-(CH2)s-, Ci1 -6 alkyl-S02-(CH2)s-, CI-6 alkylaryl-S02-(CH2)s-; and R 12 is selected from hydrogen or C 1-8 alkyl; s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
6. The method of Claim 5, wherein the compound is selected from 2-Oxo-3-[2-(5 ,6,7 ,8 -tetrahydro -naphthyridin-2-yl)ethyllpiperidin- 1 -yl-acetyl-3(S)-pyridin-3 -yl-p3-alanine ethyl ester; 2-Oxo-3-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyllpiperin- 1 -yl -acetyl-3 (S)-pyridin-3 -yl-p-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro[1 l,8]-naphthyridmn-2- yl)ethyllpyrrolidin-1I-yl)acetyl-3(S )-alkynyl- f-alanine ethyl ester; 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2- yl)ethyllpyrrolidin- 1-yl)acetyl -3 (S)-alkynyl -f-alanine; 2-Oxo-3 ,6 ,7,8-tetrahydro -naphthyridin-2-yl)ethyl] pyrrolidin-1-yl)acety1-3(S)-pyridin-3-yl-p-alanine ethyl ester; 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro [1 -naphthyridmn-2- yl)ethyllpyrrolidin- 1-yl)acetyl-3(S)-pyridin-3-yl-p-alanine; -WO 98/08840 WO 9808840PCT1US97/14912 216 2-Oxo-3(R)-[2-(5 ,6,7,8-tetrahydro[ 1 -naphthyridin-2- yl)ethyllpyrrolidin- 1 -y)acetyl-3 (S )-alkynyl- p-alanine ethyl ester; 2-Oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro[l1,8] -naphthyridin-2- yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-p-alanine; 2-Oxo-3(R)- ,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyl] pyrrolidin- 1-yl)acetyl-3 (S)-pyridmn-3-yl -f-alanine ethyl ester; 2-Oxo-3(R)- ,6,7 ,8-tetrahydro [1 -naphthyridin-2- yl)ethyllpyrrolidin-1-I-y)acetyl-3(S)-pyridin-3 -yl -J-alanine; Ethyl 2-oxo-3 ,6,7 ,8-tetrahydro[ 1 ,]naphthyridin-2-yl)ethyl] tetrahydropyrimidin-l-yl-acetyl-3 (S )-pyridin-3 -yl-fp-alanine; 2-Oxo-3- ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl I ethyl] tetrahydropyrimidin- 1-yl-acetyl-3 (S )-pyridin-3 -yl-p-alanine; Ethyl 2-oxo-3- ,6 ,7,8 -tetrahydro [1 ,8]naphthyridin-2- yl)ethyl]imidazolidin-l-yl-acetyl-3 (S)-pyridin-3 -y1-p-alanine; 2-Oxo-3 ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl I ethyl] imidazolidin- 1 -yl-acetyl-3 (S)-pyridin-3 -yl-j3-alanine; Ethyl 2-oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro naphthyridin-2- 2-Oxo-3 ,6 ,7,8-tetrahydro[ 1 ,8]naphthyridin-2- Ethyl 3 t2-oxo-3 ,8-tetrahydro- [1 ,8]naphthyridin-2- ylmethyl)-amino] -pyrrolidin- l-yl I-acetylamino)-3-(S)-pyridin-3 -yl- propionic acid; WO 98/08840 PTU9/41 PCTfUS97/14912 217 ,6,7,8-tetrahydro- naphthyridin-2-ylmethyl)- aminolpyrrolidin-1 -yl }-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3- {2-[6-Oxo-l1-(5,6,7,8-tetrahydro-[1I,8]naphthyridin-2-ylmethyl)- hexahydro-(3aS, 6aS)pyrrolol3 ,4-blpyrrol-5-yl] -acetylamino pyridin-3-yl-propionic acid; 3-1{2-[6-Oxo- 1 -(5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-2-ylmethyl)- hexahydro-(3aR, 6aR)pyrrolol3 ,4-blpyrrol-5 -yl] -acetylamino pyridmn-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3 ,6,7,8-tetrahydro -naphthyridin-2-yl)- ethyllpyrrolidn- 1 -yl)acetyl-3 (S )-alkyny1-p-alanmne ethyl ester; 2-Oxo-5(R)-methyl-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2- yl)ethyllpyrrolidin- 1-yl)acety1-3(S)-alkyny1-fo-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5 ,6 ,7,8-tetrahydro[ -naphthyridin-2-yl)- ethyllpyrrolidin- 1-yl)acetyl-3(S)-pyridin-3 -yl-p-alanine ethyl ester; 2-Oxo-5(S)-benzyl-3 ,6,7 ,8-tetrahydro -naphthyridin-2- yl)ethyllpyrrolidin- 1 -y1)acetyl-3(S)-pyridin-3-yl-p-alanine; 5(R)-Methyl-2-oxo-3(S)-[2-(5 ,6 ,7,8-tetrahydro[ -naphthyridin-2- ylmnethyl)-amnino]pyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-p-alanine ethyl ester; (R)-Methyl-2-oxo-3 (S ,6 ,7 ,8-tetrahydro [1 -naphthyridin-2- ylmethyl)-amino]pyrrolidin- 1 -yl)acetyl-3 (S )-alkynyl-p-alanine; 3 (S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2- J 2-oxo-3 ,6,7 ,8 tetrahydro-[ [1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin- Il-yl I acetylamino)-propionic acid ethyl ester; WO 98/08840 PTU9/41 PCTIUS97/14912 218 3 (S)-(2,3-Dihydro-benzofuran-6-yl)-3 {2-oxo-3(S)- ,6,7 ,8 tetrahydro-[ 1 ,8]naphthyridin-2-yl)-ethyl]-pyrrolidin- Il-yl I1- acetylamino)-propionic acid; 3- ,6,7 ,8-tetrahydro-[ 1,8]naphthyridin-2-yI)-ethyl] pyrrolidin- 1-yl)-acetylamino I-3(S)-quinolin-3 -yl-propionic acid; 3-(2-(5(S)-Ethyl-2-oxo-3(S)- ,6,7 ,8-tetrahydro-[ 1 ,8]naphthyridmn-2- yl)-ethyl] -pyrolidin- I -yl)-acetylamino)-3-(S )-quinolin-3-yl-propionic acid trifluoroacetate; 3 {6-Methyl-2-oxo-3-[(5 ,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-2- ylmethyl)-amino] -2H-pyridin-I -yl I -acetylamino)-3(S)-pyridin-3 -yl- propionic acid bis trifluoroacetate; or {6-Methyl-2-oxo-3 ,6,7,8-tetrahydro-[ [1,8]napthyridin-2- yhnethyl)-amino]-2H-pyridin-1 -ylII -acetylamino)-3(S)-pyridin-3-yl- propionic acid ethyl ester; and the pharmaceutically acceptable salts thereof.
7. The method of Claim 6, wherein the compound is selected from 2-Oxo-3 ,6,7 ,8-tetrahydro -naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyl-3 (S)-pyridin-3 -yl-p-alanine trifluoroacetate; 2-Oxo-3 ,6,7 ,8-tetrahydro [1 -naphthyridin-2- yl)ethyllpyrrolidin- 1-yl)acetyl-3 -alkynyl -f3-alanmne; 2-Oxo-3(S)- ,6,7 ,8-tetrahydro 11,8] -naphthyridmn-2- yl)ethyllpyrrolidin-1 -y1)acetyl-3(S)-pyridin-3-yl-o-alanine; WO 98/08840 PTU9/41 PCTIUS97/14912 -219- 2-Oxo-3 ,6,7,8-tetrahydro 1,8] -naphthyridin-2- yl)ethyllpyrrolidin- 1 -yl)acety1-3(S)-alkyny1-p-alanine; 2-Oxo-3 ,6,7 ,8-tetrahydro[ 1 -naphthyridin-2- yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-pyridin-3 -yl-p-alanine; 2-Oxo-3 ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl I ethyl] imidazolidin- 1 -yl-acetyl-3-(S)-pyridin-3-yl-3-alanine; 2-Oxo-3 ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-y1 ethyl] tetrahydropyrimidin- 1 -yl-acetyl-3 -(S)-pyridin-3 -y1-P-alanine; 2-Oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro[ [1,8]naphthyridin-2- 3-(2-1{2-oxo-3 ,6,7 ,8-tetrahydro-[ [1,8]naphthyridin-2-ylmethyl)- amrino] pyrrolidin- l-yl I-acetylamino)-3 -(S)-pyridin-3 -yl-propionic acid; 3- {2-[6-Oxo-l1-(5,6,7,8 -tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)- hexahydro-(3aS, 6aS)pyrrolo[3 ,4-b]pyrrol-5-yl] -acetylamino pyridin-3 -yl-propionic acid; 3-1{2-[6-Oxo-l1-(5,6,7 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)- hexahydro-(3aR, 6aR)pyrrolo[3 ,4-b]pyrrol-5-yl] -acetylamino pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(5 ,6 ,7,8-tetrahydro -naphthyridin-2- yl)ethyl]pyrrolidin-1 -yl)acety1-3(S)-alkyny-p3-alanine; 2-Oxo-5(S)-benzyl-3 ,8-tetrahydro -naphthyridin-2- yl)ethyl]pyrrolidin-1I-yl)acety1-3(S)-pyridm-3-y-p-alanine; 5(R)-Methyl-2-oxo-3(S)- ,6 ,7,8-tetrahydro[ 1,8] -naphthyridin-2- ylmethyl)-aminolpyrrolidin- 1-y1)acety1-3(S)-alkynyl-p-alanine; or WO 98/08840 PCT/US97/14912 -220- 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2- 2-oxo-3(S)-[2-(5,6,7,8- tetrahydro-[ 1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin- 1-yl} acetylamino)-propionic acid; and the pharmaceutically acceptable salts thereof.
8. The method of Claim 1, wherein the vitronectin receptor antagonizing effect is an av33 antagonizing effect.
9. The method of Claim 8 wherein the av33 antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth. The method of Claim 9, wherein the av33 antagonizing effect is the inhibition of bone resorption.
11. The method of Claim 1, wherein the vitronectin receptor antagonizing effect is an av35 antagonizing effect.
12. The method of Claim 11 wherein the antagonizing effect is selected from inhibition of: restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
13. The method of Claim 1, wherein the vitronectin receptor antagonizing effect is a dual cavp3/avp5 antagonizing effect.
14. The method of Claim 13, wherein the dual antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth. 221 A method of treating or preventing a condition mediated by antagonism of a vitronectin receptor in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound defined in the method of any one of Claims 1 to 14.
16. The method of Claim 15, wherein the compound is defined in the method of Claim 1.
17. The method of Claim 15 or Claim 16, wherein the condition is selected from the group consisting of osteoporosis or cancer.
18. A method of inhibiting bone resorption in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a S compound defined in the method of any one of Claims 1 to 14. S: 19. The method of Claim 18, wherein the compound is defined in the method of Claim 1.
20. A method of treating osteoporosis in a mammal in need thereof, the method 15 comprising administering to the mammal a therapeutically effective amount of a compound defined in the method of any one of Claims 1 to 14.
21. The method of Claim 20, wherein the compound is defined in the method of Claim 1.
22. A compound of the formula 0 R R 9 II CO2R12 X-Y-Z-(CH 2 )n-C-N C 2 H lORR S* wherein X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with one or more groups chosen from R 2 R 15 or R16; Y is selected from. [R:\LIBAA08067.doc:kww WO 98/08840 PTU9/41 PCTIUS97/14912 -222- R 3 0 0 0 (CH 2 )f-C-N-(CH 2 )Em -(CH 2 1 -4 -C -(CH 2 )T- -(CH 2 )jS(0)q-(CH 2 (CH 2 )~-t0-(CH 2 or (OH 2 Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, 0 and S, and wherein the ring system is either unsubstituted or substituted with one or more groups independently selected from R 4 R 5 R 6 and R 7 provided that Z is not a 6-memberedmonocyclic aromatic ring system, an isoxazoline ring or an isoxazole ring; R 1, R 2 R 4 R 5 R 1 3 R 14 R 15 and R 1 6 are each independently selected from hydrogen, halogen, C I 10 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl. Cl-6 alkyl, aryl, aryl Cl-8 alkyl, amino, amino C1-8 alkyl, CI-3 acylamino, C1-3 acylamino C1-8 alkyl, (CI-6 alkyl)qamino, (C1-6 alkyl)qamino Cl-8 alkyl, Ci1-4 alkoxy, CI -4 alkoxy CI -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl -6 alkyl, Ci 1 -3 alkoxycarbonyl, Ci -3 alkoxycarbonyl Ci -6 alkyl, hydroxycarbonyl- C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, CI-6 alkyloxy- Ci -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)q, (CQ-8 alkyl)qaminocarbonyl, WO 98/08840 PTU9/41 PCT/US97/14912 223 C I -8 alkyloxycarbonylamino, (Ci1 -8 alkyl)qaminocarbonyloxy, oxo, (aryl Ci1 -8 alkyl)qamino, (aryl)qamino, aryl Ci1-8 alkylsulfonylamino or C 1-8 alkylsulfonylamino; R 3 is selected from hydrogen, aryl, aryl-(CH2)p-. hydroxyl, C 1-5 alkoxy, aminocarbonyl, C3-8 cycloalkyl, amino Ci1 -6 alkyl, (aryl)qaminocarbonyl, (aryl CI-5. alkyl)qaminocarbonyl, hydroxycarbonyl Ci1 -6 alkyl, C 1-8 alkyl, aryl Cl1-6 alkyl, (C 1-6 alkyl)qamino C 1-6 alkyl, (aryl C 1-6 alkyl)qamino C 1-6 alkyl, C 1 -8 alkylsulfonyl, Ci -8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci -8 alkoxycarbonyl, Ci1 -8 alkylcarbonyl, arylcarbonyl, aryl CI -6 alkylcarbonyl, (Ci -8 alkyl)qaminocarbonyl, aminosulfonyl, Ci1 -8 alkylaminosulfonyl, (aryl)qaminosulfonylamino, (aryl C1-8 alkyl)qaminosulfonyl, Ci1 -6 alkylsulfonyl, arylsulfonyl, WO 98/08840 WO 9808840PCTIUS97/14912 224 aryl C 1 -6 alkylsulfonyl, aryl C 1 -6 alkylcarbonyl, Ci1 -6 alkylthiocarbonyl, aryithiocarbonyl, or aryl Ci -6 alkyithiocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R3and R4 R 6 R 7 R 8 R 9 R 1 0 and R I are each independently selected from hydrogen, aryl, aryl-(CH2)p-, aryl-(CH2)n-O-(CH2)m-, aryl-(CH2)n -S(O)q-(CH2)m-, aryl-(CH2)n-C(O)-(CH2)m-, aryl-(CH2)n-C(O)-N(R 3 aryl-(CH2)n-N(R 3 aryl-(CH2)n-N(R 3 halogen, hydroxyl, Ci1 -8 alkyicarbonylamnino, aryl CI-5 alkoxy, C1 -5 alkoxycarbonyl, (Ci -8 aikyl)qaminocarbonyl, Cp-6 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (Ci1 -6 alkyl)qamino, amino Ci1 -6 alkyl, arylaminocarbonyl, aryl Ci-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci -6 alkyl, hydroxycarbonyl, -WO 98/08840 PTU9/41 PCTIUS97/14912 -225- hydroxycarbonyl C1-6 alkyl, C 1-8 alkyl, either unsubstituted or substituted, with one or more Is groups selected from: halogen, hydroxyl, Ci -5 alkylcarbonylamino, aryl Ci -5 alkoxy, Ci -5 alkoxycarbonyl, aminocarbonyl, (Cl-5 alkyl)qamino- carbonyl, CI-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, (CI -3 alkyl)qamnino, amino CI -3 alkyl, (aryl)qaminocarbonyl, (aryl CI -5 alkyl)qaminocarbonyl, aminocarbonyl, amninocarbonyl Ci1 -4 alkyl, hydroxycarbonyl or hydroxycarbonyl Cl-5 alkyl, CH=-C-(CH2)s-, Ci1 -6 alkyl-C=-C-(CH2)s-, C3-7 cycloalkyI-C-=C-(CH2)s-, aryl-C=-C-(CH2)s-, Cl..6 alkylaryl-C=-C-(CH2)s-, CH2=-CH-(CH2)s-, Ci -6 alkyl-CH=CH-(CH2)S-,, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, C1-6 alkylaryl-CH=CH-(CH2)s-, C1-6 alkyl-S02-(CH2)s-, C1 -6 alkylaryl-S02-(CH2)s-, C 1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)qamino C1-6 alkyl, (aryl)qamino, (aryl)qamino C1-6 alkyl, (aryl C1-6 alkyl)qamino, (aryl Ci1 -6 alkyl)qamino Ci1 -6 ailkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (Ci -6 alkyl)qaminocarbonyloxy, Ci1 -8 alkylsulfonylamnino, WO 98/08840 WO 9808840PCTIUS97/14912 226 arylsulfonylamino, Cl1-8 alkylsulfonylamino Ci1 -6 alkyl, arylsulfonylamino C 1-6 alkyl, aryl Ci -6 alkylsulfonylamino, aryl C 1-6 alkylsulfonylamino Ci1 -6 alkyl, Ci -8 alkoxycarbonylamino, Ci -8 alkoxycarbonylamino Ci -8 alkyl, aryloxycarbonylamino Ci -8 alkyl, aryl Ci -8 alkoxycarbonylamino, aryl CI-8 alkoxycarbonylamino CI-8 alkyl, C 1-8 alkylcarbonylamino, Cl-8 alkylcarbonylamino CI-6 alkyl, arylcarbonylamino Ci -6 alkyl, aryl Ci -6 alkylcarbonylamino, aryl Cp.6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino Cl-6 alkyl, (Ci -8 alkYl)qaminocarbonylamino, (Ci -8 alkyl)qaminocarbonylamino Ci -6 alkyl, (aryl)qaminocarbonylamino Ci -6 alkyl, (aryl Ci-8 alkYl)qaminocarbonylainino, (aryl CI-8 alkyl)qaminocarbonylamino Cl-6 alkyl, aminosulfonylamino Ci1 -6 alkyl, (Ci -8 alkyl)qaminosulfonylamino, (C1-8 alkyl)qaminosulfonylamino Ci -6 alkyl, (aryl)qaminosulfonylamino CI -6 alkyl, (aryl CI-g alkyl)qaminosulfonylaniino, (aryl C1-8 alkyi)qaminosulfonylamino CI-6 alkyl, Ci1 -6 alkylsulfonyl, C1-6 alkylsulfonyl CI-6 alkyl, arylsulfonyl Ci -6 alkyl, aryl Ci1 -6 alkylsulfonyl, aryl Ci1 -6 alkyisulfonyl Ci1 -6 alkyl, Ci -6 alkylcarbonyl, Ci1 -6 alkylcarbonyl Ci1 -6 alkyl, WO 98/08840 PCTIUS97/14912 -227 arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino Ci-6 alkyl, aryl Cl-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1-8 alkyl)qaminocarbonyl C1-6 alkyl, (aryl)qaminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)qaminocarbonyl, or (aryl C1-8 alkyl)qaminocarbonyl C1-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 13 and R1 4 and provided that the carbon atom to which R 8 and R 9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R10 and R 1 1 are attached is itself attached to no more than one heteroatom; R 12 is selected from hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, C1-8 alkylcarbonyloxy C1-4 alkyl, aryl C1-8 alkylcarbonyloxy Cl-4 alkyl, C1-8 alkylaminocarbonylmethylene, or C1-8 dialkylaminocarbonylmethylene; m, s and t are each independently an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and the pharmaceutically acceptable salts thereof. -228- 23 Z is selected from The compound of ClaiM 2 2, wheremi R 7 u e 6 R4R R7 ;N' H 7Q R 4 ~N -229- R 4 RI 6 0 S 0 S OSSO S S S R 7 R 4 R 6 and the pharmaceutically acceptable salts thereof. 6 *0 5 0O56 *5005 *56SS @5 6 *0 5 OSSS 0O S S OS from
24. The compound of Claim 23 wherein Z is selected 4 R0 R 4 o 0 i/L NN N 0 0 0~- 0[ yrl N 0 230 0 R 4 H to* @0 0 *see to 0 0 0SO 0 0 and the pharmaceutically acceptable salts thereof.
25-. Th~e compound of Claim 2 4 of the- formula 0 R CH 2 CNWJ\C2 wherein X is selected from WO 98/08840 PCT/US97/14912 231 NN N s~*or N7 H H H Y is selected from -(CH2)r- or -(CH2)m-NR 3 -(CH2)t-; R 3 is selected from hydrogen, aryl-(CH2)p-, C 1 -5 alkoxycarbonyl, C3-8 cycloalkyl, (aryl)qaminocarbonyl, (aryl C 1.5 alkyl)qaminocarbonyl, Ci-g alkyl, aryl CI -6 alkyl, Ci1 -8 alkylsulfonyl, arylsulfonyl, aryl Ci -6 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci -8 alkoxycarbonyl, Ci1 -8 alkylcarbonyl, arylcarbonyl, aryl Ci1 -6 alkylcarbonyl, (Cp-8 alkyl)qaminocarbonyl, C1-6 alkylsulfonyl, or aryl Ci -6 alkylcarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R 1 3 and Ri 4 R 4 is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl CI-.6 alkyl, aryl or aryl Ci-8 alkyl, -232- R 8 is selected from hydrogen, aryl, aryl-(CH2)p-, CH=-C-(CH2)s-, Cl1 -6 a~kyI-C=-C-(CH2)s-, :C3-7 cycloalky1-C-=C-(CH2)s-, arYl-C=-C-(CH2)s-, 9:06: 10 CI-6 alkylaryl-C=C-(CH2)s-, CH2=CH-(CH2)s-, C1-6 alkyl-CH=CH-(CH2)s-, *foe f C3-7 cycloalkyl-CH=CH-(CH2)s- aryl-CH=CH-(CH2)s-, 15 CI -6 alkylaryl-CH=CH-(CH2)s-, Ci -6 alkyl-S02-(CH2)s-, Cl-6 alkylaryl-S02-(CH2)s-; and sees r is an integer from 0 to 3; :*.and the pharmaceutically acceptable salts thereof. 26 The compound of Claim 25 of the formula N M-N Y-Z-CH 2 CNH H wherein Z is selected from WO 98/08840 PTU9/41 PCT/US97/14912 233 o 00 rh-\ N- o0 N NH N Nor\ 00 0 R 8 is selected from hydrogen, -o F <0-O> Nz 0N H ifldolyl-(CH2)p-, CHEl-C-(CH2)s-, Ci -6 alkyl-C=-C-(CH2)s-, C3-7 cycloalkyl-C=-C-(CH2)s-, aryl-C=-C-(CH2)s-, Ci -6 alkylary-C=-C-(CH2)s-, CH2-CH-(CH2)s-, Ci -6 alkyl-CH=CH-(CH2)s-, C3-7 cycloalkyl-CH=CH-(CH2)s-, aryl-CH=CH-(CH2)s-, Cl-6 alkylaryl-CH=CH-(CH2)s-, 234 Ci1 -6 alkyl-S02-(CH2)s-, C1-6 alkylaryl-S02-(CH2)s-; and R 1 2 is selected from hydrogen or C 1-8 alkyl; and s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof. The compound of Claim 2 6 selected from :10 2-Oxo-3 ,6,7 ,8 -tetrahydro 1, 8] -naphthyri din-2-yl) ethyl]lpiperi din 1 -y1-acetyl-3(S)-pyridin-3-yl-p-alanine ethyl ester; 2-Oxo-3-[2-(5,6,7 ,8 -tetrahydro -naphthyridin-2-yl)ethyllpiperin- 1 -yl-acetyl-3(S)-pyridin-3 -yl-p-alanine triflu oro acetate; i 2-Oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro [1 -naphthyridin-2- yl)ethyl]pyffolidin- 1-yl)acetyl-3 (S )-alkyny1-p-alanine ethyl ester; 2-Oxo-3(S)-[2-(5 ,6,7,8-tetrahydro [1 -naphthyridin-2- yl)ethyllpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-p-alanine; 2-Oxo-3 ,7 ,8-tetrahydro -naphthyridin-2-yl)ethyl] din- 1 -yl)acetyl1-3 -pyri din- 3 -yl -p-alanine ethyl ester; 2 -Oxo- (5 ,6,7 ,8 -tetrahydro 1, 8] -naphthyridin-2- ylI)ethyl] pyrrolidin- 1 -yl)acetyl -3 yridin-3 -yl -0 -al anine; 2-Oxo -3 ,6,7,8 -tetrahydro 1, 8] -naphthyridin-2- yl)ethyllpyffolidin- 1-yl)acety1-3(S)-alkynyl-p-alanine ethyl ester; 3 0 2-Oxo-3(R)-[2-(5 ,6,7,8-tetrahydro [1 -naphthyridin-2- yl)ethyl]pyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-p-alanine; WO 98/08840 PCTIUS97/14912 235 2-Oxo-3 ,8-tetrahydro[ 1,8] -naphthyridin-2-yl)ethyl] pyrrolidin- 1-y1)acetyl-3 (S)-pyri din 3-yl-p- alanine ethyl ester; 2-Oxo-3 ,6,7,8-tetrahydro[ 1,8] -naphthyridin-2- yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-pyridmn-3-yl-p-alanine; Ethyl 2-oxo-3 ,6,7 ,8-tetrahydro[ 1,8]naphthyridin-2-yl)ethyl]- tetrahydropyrimidin-l-yl-acetyl-3 (S)-pyridin-3 -yl-p-alanine; 2 -Ox o-3 2-(5 ,8-tetrahydro 1, 8] naphthyri din -2-yl I ethyl] tetrahydropyrimidin- 1 -yl-acetyl-3 (S)-pyridin-3 -yl-p-alanine; Ethyl 2-oxo-3-[2-(5 ,6,7 ,8-tetrahydro[ 1,8]naphthyridin-2- yl)ethyl]imidazolidin-l-yl-acetyl-3 (S )-pyridin-3 -yl-f3-alanine; 2-Oxo-3-[2-(5 ,6,7,8-tetrahydro[ 1,8]naphthyridin-2-ylI )ethyl] imidazolidin- 1-yl-acetyl-3 (S)-pyridin- 3-yl-p-alanine; Ethyl 2-oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8]naphthyridmn-2- y1)ethy1]pyrrolidin-1-y1)acetyl-3(R)-(2-ethyildol- 3 -yl)-p-alalile; 2-Oxo-3(R)-[2-(5 ,6,7 ,8-tetrahydro [1 ,8]naphthyridin-2- yl)ethyllpyrrolidmn-l-yl)acetyl-3 (R)-(2-ethylindol-3-yl)-p-alanine; Ethyl 3 2-oxo-3(S)-[(5 ,6,7 ,8-tetrahydro- [1 ,8]naphthyridin-2- ylmethyl)-amino] -pyrrolidin- l-yI }-acetylamino)-3 )-pyridin-3 -yl- propionic acid; 3 2-Oxo-3(S)-[(5 ,6,7 ,8-tetrahydro-1 ,8]naphthyridin-2-ylmethyl)- amino] pyrrolidin- 1 -yl I -acetylamino)-3 -(S)-pyridin-3 -yl-propionic acid; v ~3-f 2- [6-Oxo-l1-(5,6,7 ,8-tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)- hexahydro-(3aS, 6aS)pyrrolo[3 ,4-blpyrrol-5-yl] -acetylamino pyridin-3-yl-propionic acid; WO 98/08840 PCTIUS97/14912 236 3-{f 2-[6-Oxo- 1 ,8-tetrahydro-[ [1,8]naphthyridin-2-ylmethyl)- hexahydro-(3aR, 6aR)pyrrolo[3 ,4-bjpyrrol-5-yl] -acetylamino1-3 pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3 ,6,7,8-tetrahydro[ -naphthyridin-2-yl)- ethyllpyrroli din- I -yl) acetyl -3 (S )-alkyny1 -alanine ethyl ester; 2-Oxo-5(R)-methyl-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1 -naphthyridin-2- yl)ethyllpyrrolidin- 1 -yl)acetyl-3 (S)-alkyny1-fp-alanine; (S)-benzyl-3(S)-[2-(5 ,6,7 ,8-tetrahydro -naphthyridin-2-yl)- ethyl] pyrrolidin- 1 -yl)acetyl-3 (S)-pyridin-3 -yl- P-alanine ethyl ester; 2-Oxo-5 (S)-benzyl-3 ,6,7,8-tetrahydro -naphthyridin-2- yl)ethyll pyrroli din- 1 -yl)acetyl- 3(S)-pyridin -3 -yl P-alanine; (R)-Methyl-2-oxo-3 ,6 ,7 ,8-tetrahydro[ 1,8] -naphthyridin-2- ylmethyl)-amnino]pyrrolidin- 1-yl)acetyl- 3(S)-alkynyl-J3-alanine ethyl ester; (R)-Methyl-2-oxo-3(S)-[2-(5 ,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2- ylmethyl)-aminolpyrrolidin- 1-yl)acetyl-3 (S)-alkynyl-fo-alanine; 3 -Dihydro-benzofuran-6-yl)-3 2-oxo-3(S)-[2-(5 ,6,7 ,8- tetrahydro- 1 naphthyridin-2-yI) -ethyl] -pyrrolidin- Il-yl 1 acetylamino)-propionic acid ethyl ester; 3 -Dihydro-benzofuran-6-yl)-3 2-oxo-3 ,6 ,7,8- tetrahydro- 1, ,8]naphthyri din-2-yl) -ethyl]I -pyrrolidin- 1 -yl I acetylamino)-propionic acid; 3- {2-(2-Oxo-3 ,6,7,8 -tetrahydro- [1 ,8]naphthyridin-2-yl)-ethyl] pyrrolidin- 1-yl)-acetylamino I-3(8 )-quinolin- 3-yl-propionic acid; 237 3 (S)-Ethyl-2-oxo-3 (S)-[2-(5,6,7,8-tetrahydro-[ 1,8]naphthyridin-2- yl)-ethyl] -pyrolidin- 1 -yl)-acetylamino)-3-(S )-quinolin-3-yl-propi onic acid trifluoroacetate; 3 6-Methyl-2-oxo-3 ,8-tetrahydro-[ 1 ,8]naphffiyridin-2- ylmethyl)-amino] -2H-pyridin- 1-.yl) -acetylamino)-3 (S)-pyridin-3 -yl 4, 00propionic acid bis trifluoro acetate; or 10 {6-Methyl-2-oxo-3 8-tetrahydro-[ 1,8]napthyridin-2- ylmethyl)-amino] -2H-pyridin- 1-yl }-acetylamino)-3 (S )-pyridin-3 -yl- D D propionic acid ethyl ester; DO** and the pharmaceutically acceptable salts thereof. 00o
28. Thbe compound of Claim 2 7, selected from 0002-Oxo-3 ,6,7 ,8 -tetrahydro[ 1,8] -naphthyridin-2-yl)ethyllpiperifl- 0 yl-acetyl-3 (S)-pyridin-3 -yl-Jp-alanine trifluoroacetate; 0 202-Oxo-3 ,6,7 ,8 -tetrahydro[ 1,8] -naphthyridin-2- 0000yl)ethyl]pyrrolidin- 1 -yl)acetyl-3 (S)-alkynyl-j3-alanine; 600*00 !00 00 2-Oxo-3(S)- ,6,7 ,8 -tetrahydro[ 1,8] -naphthyridin-2- 25 yl)ethyl]pyrrolidin- I -yl)acetyl-3 (S)-pyridin-3-yl-p-alanine; 2-Oxo-3 ,6,7 ,8-tetrahydro -naphthyridin-2- yl)ethyllpyrrolidin- 1-yl)acetyl-3(S)-alkynyl-p-alanine; -2-Qxo -R){2[-:(;5-6,7,8-tetrahydro[ I '8 nahthyjdn- 2 T. yl)ethyl]pyrrolidin-.1 -yl)acetyl-3(S)-pyridin-3-yl-3-alaflile; 2-Oxo-3 ,6,7 ,8-tetrahydro[ 1 ,8]naphthyridin-2-yl I ethyl] imnidazolidin- 1 y-ctl3()prii--lpaaie WO 98/08840 PCTIUS97/14912 238 2-Oxo-3-[2-(5 ,6,7,8-tetrahydro[ 1 ,8]naphthyridin-2-yl i ethyl] tetrahydropyrimidin- 1 -yl-acetyl-3 -(S)-pyridin-3 -y1-p-alanine; 2-Oxo-3(R)- ,8-tetrahydro[ 1 ,8]naphthyridin-2- 3 ,6,7,8-tetrahydro-[ 1,8 ]naphthyridin-2-ylmethyl)- aminolpyrrolidin- l-yl I-acetylamino)-3 )-pyridin-3 -yl-propionic acid; 2-[6-Oxo-l1-(5,6,7 ,8-tetrahydro-[ 1,8]naphthyridin-2-ylmethyl)- hexahydro-(3aS, 6aS)pyrrolo[3 ,4-b]pyrrol-5-yl] -acetylamino pyridin-3-yl-propionic acid; or 3-12- [6-Oxo- 1 ,8-tetrahydro- [1 ,8]naphthyridin-2-ylmethyl)- hexahydro-(3aR, 6aR)pyrrolol3 ,4-b]pyrrol-5 -yl] -acetylamino pyridin-3 -yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(.5,6,7 ,8-tetrahydro[ 1,8] -naphthyridin-2- yI)ethyl]pyrrolidin- 1 -yl)acetyl-3 (S)-alkyny1-o-alanmne; 2-Oxo-5(S)-benzyl-3 ,6,7,8-tetrahydro 1,8] -naphthyridin-2- yl)ethyllpyrrolidin- 1 -y1)acetyl-3(S)-pyridin-3-yl-fo-alanine; 5(R)-Methyl-2-oxo-3(S)-[2-(5 ,6 ,7,8-tetrahydro[ 1,8] -naphthyridin-2- ylmethyl)-amino]pyrrolidin- 1-yl)acetyl-3 (S )-alkyny1-p-alanine; or -Dihydro-benzofuran-6-yl)-3-(2- J 2-oxo-3(S)-[2-(5 ,6,7 ,8 tetrahydro-[ [1,8]naphthyridin-2-yl)-ethyl] -pyrrolidin- l-yl acetylamino)-propionic acid; and the pharmaceutically acceptable salts thereof. 239
29. A pharmaceutical composition comprising the compound of Claim 22 and a pharmaceutically acceptable carrier. A pharmaceutical composition made by combining a compound of Claim 22 and a pharmaceutically acceptable carrier.
31. A process for making a pharmaceutical composition comprising combining a compound of Claim 22 and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising a compound of any one of Claims 22 to 28 and a pharmaceutically acceptable carrier.
33. A method of eliciting a vitronectin receptor antagonizing effect in a mammal in 10 need thereof, the method comprising administering to the mammal a therapeutically S effective amount of a compound of any one of Claims 22 to 28 or of a composition of any S one of Claims 29, 30 or 3 2 S* 34. A method of treating or preventing a condition mediated by antagonism of a vitronectin receptor in a mammal, the method comprising administering to the mammal a 15 therapeutically effective amount of a compound of any one of Claims 22 to 28 or of a composition of any one of Claims 29, 30 or 32. The method of Claim 33 or Claim 34, wherein the composition of Claim 29 is administered to the mammal.
36. A method of inhibiting bone resorption in a mammal, the method comprising .20 administering to the mammal a therapeutically effective amount of a compound of any one of Claims 22 to 28 or of a composition of any one of Claims 29, 30 or 32.
37. The method of Claim 36, wherein the composition of Claim 29 is administered see' 0 to the mammal.
38. A method of treating osteoporosis in a mammal, the method comprising 25 administering to the mammal a therapeutically effective amount of a compound of any one of Claims 22 to 28 or of a composition of any one of Claims 29, 30 or 32.
39. The method of Claim 38, wherein the composition of Claim 29 is administered to the mammal. A method of treating tumor growth in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of any one of Claims 22 to 28 or of a composition of Claim 32 and one or more agents known to be cytotoxic or antiproliferative.
41. The method of Claim 40, wherein the compound of Claim 22 is administered to the mammal. [R:\LIBAA]08067.doc:kww 240
42. A compound defined in the method of any one of Claims 1 to 18 when used to elecit a vitronectin receptor antagonizing effect in a mammal.
43. Use of a compound defined in the method of any one of Claims 1 to 18 in the manufacture of a medicament to elecit a vitronectin receptor antagonizing effect in a mammal.
44. A compound defined in the method of any one of Claims 1 to 18 when used to treat or prevent a condition mediated by antagonism of a vitronectin receptor in a mammal. Use of a compound defined in the method of any one of Claims 1 to 18 in the manufacture of a medicament to treat or prevent a condition mediated by antagonism of a vitronectin receptor in a mammal. S.. 46. A compound defined in the method of any one of Claims 1 to 18 when used to Sinhibit bone resorption in a mammal.
47. Use of a compound defined in the method of any one of Claims 1 to 18 in the manufacture of a medicament to inhibit bone resorption in a mammal. 15 48. A compound defined in the method of any one of Claims 1 to 18 when used to treat osteoporosis in a mammal.
49. Use of a compound defined in the method of any one of Claims 1 to 18 in the manufacture of a medicament to treat osteoporosis in a mammal. Dated 22 June, 2000 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON *0
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