JP2003506452A - Vitronectin receptor antagonists useful for the treatment of stroke - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of vitronectin receptor antagonists for the treatment of stroke.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to the use of antagonists of the vitronectin receptor for the treatment of stroke.

[0002] (Background technology)   Integrins are cytoadhesive that attach intracellular cytoskeletal components to extracellular matrix cells.
It is a superfamily of receptors. These cell surface adhesive receptors_Vβ _Three (Vitronectin receptor). Vitronectin receptor α_Vβ_ThreeIs within
It is expressed on many cells including skin, smooth muscle, osteoclasts and tumor cells, and therefore
Receptors have various functions. Α expressed on the membrane of osteoclasts_Vβ_ThreeThe receptor is
It mediates the adhesion of osteoclasts to the bone matrix, an important step in bone resorption (Ros
S. et al., J. Biol. Chem., 1987, 262, 7703). Α expressed in human aortic smooth muscle cells_V
β_ThreeReceptors mediate their migration into the neointima, a process that involves percutaneous coronary angiogenesis.
Restenosis can be reached after adulthood (Brown et al., Cardiovascular Res., 1994, 28, 1815). Addition
Thus, Okada et al. (Am. J. Pathol., 1996, 149 (1), 37)_Vβ_ThreeIs a police officer
Playing a role in remodeling after local anemia in whole and infarct
Suggest. In a primate study of transient non-human forebrain ischemia, α_Vβ_ThreeReceptor
Was up-cured early in an anemia event.   Surprisingly, vitronectin receptor antagonists can cause seizures and seizure-related trauma
It has been found to be useful in the treatment of post-wounds.

SUMMARY OF THE INVENTION The present invention is a novel method of treating seizures in mammals, particularly humans, which method comprises administering to a subject in need thereof an effective amount of a vitronectin receptor antagonist. I will provide a.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides a therapeutic method for treating seizures, for example protecting the central nervous system from traumatic and post-traumatic wounds associated with seizures such as prevention of neurotrauma. Methods and methods to reduce morbidity resulting from sequelae of seizures. Such methods utilize a series of antagonists that have been manufactured and evaluated as effective vitronectin receptor antagonists. Non-limiting examples of suitable vitronectin receptor antagonists include:

PCT application number PC published in WO98 / 14192 on April 9, 1998
Formula (I) described in T / US97 / 18001 (filed on October 1, 1997)
:

[Chemical 5] [In the formula:   R¹Is R⁷Or AC_0-4Alkyl, AC_2-4Alkynyl, AC _2-4 Alkynyl, AC_3-4Oxoalkynyl, AC_3-4Oxo Archi
Nil, AC_1-4Aminoalkyl, AC_3-4Aminoalkynyl, AC_{Three -4} Aminoalkynyl, which are R¹⁰Or R⁷One or more of
May be replaced by all permissible combinations of   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mO
R ', -S (O)_mNR'R ", -PO (OR '), -PO (OR')_Two, -N
O_TwoOr tetrazolyl;   Each R⁸Are independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'
OR 'or -OCR'_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C
(O) R ', C (O) NR'_TwoOr -CO_TwoR ';   R¹⁰Is H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -C
F_Three, CF_ThreeS (O)_r-, -CO_TwoR ', -CONR'_Two, A-C_0-6Al
Kill-, AC_1-6Oxoalkyl-, AC_2-6Alkenyl, AC_{2- 6} Alkynyl, AC_0-6Alkyloxy-, AC_0-6Alkylamino-
Or AC_0-6Alkyl-S (O)_r-Is;   R¹¹Is R ', -C (O) R', -C (O) NR '._Two, -C (O) OR ',
-S (O)_mR'or -S (O)_mNR '_TwoAnd   R^TwoIs

[Chemical 6]   W is-(CHR^g)_a-U- (CHR^g)_b-Is;   U does not exist, or CO, CR^g _Two, C (= CR^g _Two), S (O)_k , O, NR^g, CR^gOR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(O
R^k), C (O) CR^g _Two, CR^g _TwoC (O), CONRⁱ, NRⁱCO, OC
(O), C (O) O, C (S) O, OC (S), C (S) NR^g, NR^gC (S
), S (O)_TwoNR^g, NR^gS (O)_TwoN = N, NR^gNR^g, NR^gCR^g _Two , CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gso
Yes;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cyclo
Alkyl-C_0-6Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fAnd   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cyclo
Alkyl-C_0-6Alkyl, Ar-C_0-6Alkyl or halogen, CN,
NR^g _Two, OR^g, SR^g, CO_TwoR^g, And CON (R^g)_TwoSelected from
C substituted by 1 to 3 groups_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6 Alkyl, C_3-7Cycloalkyl-C_0-6Alkyl or (CH_Two)_kCO _Two R^gAnd   R^bAnd R^cIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het
-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen
CF_Three, OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_2,CO
(NR^f)_Two, CH_TwoN (R^f)_TwoIndependently selected from or R^bAnd
And R^cAre taken together to form a 5- or 6-membered aromatic or non-aromatic carbon or heterocycle
To form halogen, CF_Three, C_1-4Alkyl, OR^f, S (O)_kR ^f , COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_2,CO (NR^f)_TwoOh
And CH_TwoN (R^f)_TwoMay be substituted with up to 3 substituents selected from:
Or forming methylenedioxy;   Q¹, Q^Two, Q^ThreeAnd Q^FourAre independently N or CR^yHowever;
, Q¹, Q^Two, Q^ThreeAnd Q^FourAt most one is N;   R'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Shiku
Lower alkyl-C_0-6Alkyl;   R "is R ', -C (O) R' or -C (O) OR ';   R '' 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-
6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three,
OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_2,CO (NR^f)_Two , CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two,
-CF_Three, CF_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _Two Or halo, -OR^g, -SR^g, -CN, -NR^gR ", -NO_Two, -C
F_Three, R'S (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoBy
C which may be replaced by_1-6Alkyl;   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2;   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1; and   v is 0 or 1.] Is benzazepine or a pharmaceutically acceptable salt thereof.

A preferred compound of formula (I) for use in the method of the present invention is (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2-
(2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-
2-benzazepine-4-acetic acid and (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo-2- (2,2,2-tri Fluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof.

Further examples of vitronectin receptor antagonists for use in the methods of the invention include the antagonists described in the following references: International Patent Application No. PCT / US95 / 08306 (filed June 29, 1995). , 1996 1
WO96 / 00730 published on May 11, International Patent Application No. PCT / US95 / 0
8146 (filed June 29, 1995), WO 96/00574 (published January 11, 1996); International Patent Application No. PCT / US96 / 11108 (1996)
Application June 28, WO 97/01540 (published January 16, 1997);
International patent application number PCT / US96 / 20748 (filed on December 20, 1996), WO97 / 24119 (published on July 10, 1997); international patent application number P
CT / US96 / 20744 (filed on Dec. 20, 1996), WO97 / 24
122 (published on July 10, 1997); International Patent Application No. PCT / US96 / 2
0327 (filed December 20, 1996), WO97 / 24124 (published July 10, 1997); International Patent Application No. PCT / US98 / 00490 (1998)
Filed Jan. 8, 1998), WO98 / 30542 (published on Jul. 16, 1998); International Patent Application No. PCT / US98 / 19466 (filed on Sep. 18, 1998), W
O99 / 15508 (published April 1, 1999); and International Patent Application No. PC
T / US99 / 28662, WO00 / 33838 (published June 15, 2000). Preferred compounds described in International Patent Application WO 00/33838 are (S) -1
0,11-Dihydro-3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10- It is acetic acid. Such compounds are useful in the methods of the invention.

The vitronectin receptor antagonists used in the methods of the invention described above are cited from published patent applications. Including methods of preparing the disclosed compounds,
Reference is made to the contents of each patent application, and the entire contents of each patent application are incorporated herein by reference. In accordance with the present invention, it has been found that administration of a vitronectin receptor antagonist to stroke patients minimizes exacerbation of infarction and helps prevent second stroke. During ischemic tissue trauma, such as in stroke, most of the ischemic tissue cells are irreversibly damaged and necrotic, and the extent of the wound depends on the length of time the trauma is present, for example arterial occlusion. To do. Therefore, it is an object of the present invention to protect central nervous system neurons from such damage and necrosis during occlusions that occur during stroke and post-traumatic reperfusion.

In therapeutic use for the treatment of stroke, vitronectin receptor antagonists have been formulated into standard pharmaceutical compositions. It can be administered orally, parenterally, rectally, topically or transdermally. The pharmaceutical compositions of the vitronectin receptor antagonist are formulated as solutions or lyophilized powders for parenteral administration. The powder may be reconstituted with a suitable diluent or other pharmaceutically acceptable carrier before use. The liquid formulation may be a buffered, isotonic aqueous solution. Examples of suitable diluents are isotonic saline,
Standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral administration, but may also be used for oral administration or may be contained in a metered dose inhaler or nebulizer for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively, the vitronectin receptor antagonist may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. A pharmaceutically acceptable solid or liquid carrier may be added to fortify or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate alone or with a wax. The amount of solid carrier will vary but will preferably be from about 20 mg to about 1 g per dosage unit. The pharmaceutical preparation is milled, mixed, granulated and, if necessary, in the case of tablets,
Compressed; or crushed, mixed, and in the case of hard gelatin capsule form, made by conventional pharmaceutical techniques of filling. If a liquid carrier is used, the preparation will be in the form of syrup, elixir, emulsion or aqueous or non-aqueous suspension. Such liquid formulations may be directly administered orally or filled into soft gelatin capsules.

For rectal administration, the compounds of the invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into suppositories. The compound is administered to the subject either orally or parenterally in such a way that the concentration of drug is sufficiently effective. The pharmaceutical compositions containing the compounds are administered at an oral dose of about 0.1 to about 50 mg / kg in a manner consistent with the subject's condition. Preferably, the oral dose will be about 0.5 to about 20 mg / kg. Parenteral administration is preferred for acute treatment. An intramuscular bolus injection is also useful, but an intravenous infusion of the peptide of 5% dextrose in water or saline, or a similar formulation with suitable excipients is most effective. Typically, a parenteral dose will be about 0.0
1 to about 100 mg / kg; preferably between 0.1 and 20 mg / kg. The compounds are administered 1 to 4 times daily at a level such that the total daily dosage will reach from about 0.4 to about 400 mg / kg / day. The precise level and method of administering the compound is determined by comparing the blood level of the drug to the concentration required to obtain a therapeutic effect.
A person skilled in the art can easily determine. No unacceptable toxicological effects are expected when eprosartan is administered according to the present invention.

[0012]   (Materials and methods)   Focal cerebral ischemia:Chronic or transient focal regional ischemia or sham surgery under stereotactic control
, 18 weeks with chronic and transient MCAO, as detailed previously
Male congenital hypertensive rats (SHR) weighing 250-330 grams of age or normal
Blood pressure rat strain (Wistar-Kyoto)
(Barone FC, Price WJ, White RF, Willette RN, Feuerstein GZ (1992)
Genetic hypertension and increased susceptibility to cerebral ischemia. Neurosc Biobehav Rev  16: 219-233; Barone FC, Schmidt DB, Hillegass LM, P
rice WJ, White RF, Feuerstein GZ, Clark RK, Griswold DE, Sarau HM (1992)
 Reperfusion increases neutrophil and LTB_Four receptor binding in focal isc
hemia.Stroke 23: 1337-1348; Barone FC, Hillegass LM, Tzimas MN, Schmid
t DB, Foley JJ, White RF, Price WJ, Feuerstein GZ, Clark RK, Griswold DE
 and Sarau HM (1995) Time-related changes in myeloperoxidase activity an
d leukotriene B_Four receptor binding reflect leukocyte influx in cerebral f
ocal stroke.Mol Chem Neuropathol 24: 13-30; Barone FC, Arvin B, White R
F, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ (1997) Tumor
necrosis factor a: A mediator of focal ischemic brain injury.Stroke 28:
1233-1244). These experimental methods are similar to those established and used elsewhere.
Ri (Brint S, Jacewicz M, Kiessling M, Tanable J, Pulsinelli W (1988) Foc
al brain ischemia in the rat: Methods for reproducible neocortical infar
ction using tandem occlusion of the distal middle cerebral artery and ip
silateral common carotid arteries.J Cereb Blood Flow Metabol 8: 474-485
Buchan AM, Xue D, Slivka A (1992) A new model of temporary focal neoco
rtical ischemia in the rat.Stroke 23: 273-279; Duverger D, MacKenzie T
 (1988) The quantification of cerebral infarction following focal ischem
ia in the rat: Influence of strain, artificial pressure, blood glucose con
centration, age.J Cereb Blood Flow Metab 8: 449-461), these experimental methods
Correlation of blood flow in ischemia and infarction (Barone FC, Price WJ
, White RF, Willette RN, Feuerstein GZ (1992) Genetic hypertension and i
ncreased susceptibility to cerebral ischemia.Neurosc Biobehav Rev 16:21
9-233; Barone FC, Schmidt DB, Hillegass LM, Price WJ, White RF, Feuerst
ein GZ, Clark RK, Griswold DE, Sarau HM (1992) Reperfusion increases neu
trophil and LTB_Four receptor binding in focal ischemia.Stroke 23: 1337-134
8), Neurological defects (Barone FC, Clark RK, Price WJ, White RF, Storer
 BL, Feuerstein GZ, Ohlstein EH (1993) Neuron specific enolase increases
 in cerebral and systemic circulation following focal ischemia.Brain Re s  623: 77-82), increased cytokine expression and influence on tissue inju.
ry (Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko
PG, Feuerstein GZ (1997) Tumor necrosis factor α: A mediator of focal i
schemic brain injury.Stroke 28: 1233-1244; Wang XK, Barone FC, Aiyar NV
, Feuerstein GZ (1997) Increased interleukin-1 receptor and interleukin-
1 receptor antagonist gene expression after focal stroke.Stroke 28: 155-
162), on cell infiltration of damage, inflammation, tissue change and degradation (Clark RK, Lee EV
, Fish CJ, White RF, Price WJ, Jonak ZL, Feuerstein GZ and Barone FC (19
93) Progression of cerebral changes following middle cerebral artery occ
lusion in the rat: A quantitative planimetric, histologic and immunohist
ochemical study.Brain Res Bull 31: 565-572; Clark RK, Lee EV, White RF
, Jonak ZL, Feuerstein GZ and Barone FC (1994) Reperfusion following foc
al stroke hastens inflammation and resolution of ischemic injured tissue
.Brain Res Bull 35: 387-391; Barone FC, Hillegass LM, Price WJ, White R
F, Feuerstein GZ, Sarau HM, Clark RK, Griswold DE (1991) Polymorphonucle
ar leukocyte infiltration into cerebral focal ischemic tissue: Myelopero
xidase activity assay and histologic verification.J Neurosci Res 29: 336
-348; Barone FC, Schmidt DB, Hillegass LM, Price WJ, White RF, Feuerste
in GZ, Clark RK, Griswold DE, Sarau HM (1992b) Reperfusion increases neu
trophil and LTB_Four receptor binding in focal ischemia.Stroke 23: 1337-1348
; Barone FC, Hillegass LM, Tzimas MN, Schmidt DB, Foley JJ, White RF, P
rice WJ, Feuerstein GZ, Clark RK, Griswold DE and Sarau HM (1995) Time-r
elated changes in myeloperoxidase activity and leukotriene B_Four receptor b
inding reflect leukocyte influx in cerebral focal stroke.Mol Chem Neuro pathol  24: 13-30) and the effect of temperature on damage (Barone FC, Feuerste
in GZ, White RF (1997) Reduced brain temperature during transient focal
ischemia provides complete neuroprotection.Neurosci Biobehav Rev 21: 31-
44) Widely characterized by postings, which means a lengthy evaluation. Complete tissue wound
/ Necrosis in these experiments by 24 hours of chronic MCAO or reperfusion
Observed within 24 hours (Clark RK, Lee EV, Fish CJ, White RF, Price WJ
, Jonak ZL, Feuerstein GZ and Barone FC (1993) Progression of cerebral c
hanges following middle cerebral artery occlusion in the rat: A quantita
tive planimetric, histologic and immunohistochemical study.Brain Res Bu ll  31: 565-572; Clark RK, Lee EV, White RF, Jonak ZL, Feuerstein GZ and
 Barone FC (1994) Reperfusion following focal stroke hastens inflammatio
n and resolution of ischemic injured tissue.Brain Res Bull 35: 387-391)
. Simply put, in the case of chronic MCAO, the middle cerebral artery is permanently occluded and electrocoagulated.
Method was used to make an incision from the spine to the lateral olfactory tract at the level of the internal cerebral vein (Force 2 Ele
ctrosurgical Generator, Valley Lab Inc.). For transient MCAO with recirculation
If so, bring the MCA above the surface of the brain, stop blood flow for 160 minutes, then
(Barone FC, Price WJ, White RF, Willette RN, Feuer
stein GZ (1992) Genetic hypertension and increased susceptibility to cer
ebral ischemia.Neurosc Biobehav Rev 16: 219-233; Barone FC, Schmidt DB
, Hillegass LM, Price WJ, White RF, Feuerstein GZ, Clark RK, Griswold DE
, Sarau HM (1992) Reperfusion increases neutrophil and LTB_Four receptor bin
ding in focal ischemia.Stroke 23: 1337-1348; Barone FC, Hillegass LM,
Tzimas MN, Schmidt DB, Foley JJ, White RF, Price WJ, Feuerstein GZ, Clar
k RK, Griswold DE and Sarau HM (1995) Time-related changes in myeloperox
idase activity and leukotriene B_Four receptor binding reflect leukocyte inf
lux in cerebral focal stroke.Mol Chem Neuropathol 24: 13-30; Barone FC
, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstei
n GZ (1997) Tumor necrosis factor α: A mediator of focal ischemic brain
 injury.Stroke 28: 1233-1244). Blood flow measurements demonstrate the effectiveness of such technology
Crab, that is, blood flow is permanently reduced below 25% of baseline after chronic MCAO.
After a brief transient reperfusion of MCAO, blood flow was restored to 100% (Barone FC, Pric
e WJ, White RF, Willette RN, Feuerstein GZ (1992) Genetic hypertension a
nd increased susceptibility to cerebral ischemia.Neurosc Biobehav Rev 1
6: 219-233). Consistent response to chronic or transient focal ischemic injury (
That is, because of the consistent infarct with less change) and the focus of the study in this experiment
And selected SHR (Barone FC, Price WJ, White RF, Willette RN, Feuerst
ein GZ (1992) Genetic hypertension and increased susceptibility to cereb
ral ischemia.Neurosc Biobehav Rev 16: 219-233; Duverger D, MacKenzie T
(1988) The quantification of cerebral infarction following focal ischemi
a in the rat: Influence of strain, artificial pressure, blood glucose conc
entration, age.J Cereb Blood Flow Metab 8: 449-461; Ginsberg DM, Busto
R (1989) Rodent models of cerebral ischemia.Stroke 20: 1627-1642). Surgery
Body temperature was kept at 37 ° C using a heating pad during physical treatment, and after the head was closed,
(While recovering from anesthesia) Several hours until each animal resumes normal motor activity
Was maintained at 37 ° C. Open dura on MCA in sham-operated rats
However, the artery was not occluded. Rats were then over dosed with pentobarbital
, 1, 3, 6 and 12 hours, 1, 2, 5, 1 after being subjected to chronic MCAO treatment
At 0 and 15 days, or after reperfusion after transient MCAO, and sham
The forebrain was removed 12 hours and 5 days after surgery. Ischemic cortex (i.e.
(Ipsilateral cortex) is dissected from ipsilateral hemisphere; contralateral (control) cortex ischemia of the same rat
Not from the opposite hemisphere (Barone FC, Hillegass LM, Price WJ, White
RF, Feuerstein GZ, Sarau HM, Clark RK, Griswold DE (1991) Polymorphonucl
ear leukocyte infiltration into cerebral focal ischemic tissue: Myeloper
oxidase activity assay and histologic verification.J Neurosci Res 29:33
6-348; Barone FC, Schmidt DB, Hillegass LM, Price WJ, White RF, Feuerst
ein GZ, Clark RK, Griswold DE, Sarau HM (1992) Reperfusion increases neu
trophil and LTB_Four receptor binding in focal ischemia.Stroke 23: 1337-1348
; Barone FC, Hillegass LM, Tzimas MN, Schmidt DB, Foley JJ, White RF, P
rice WJ, Feuerstein GZ, Clark RK, Griswold DE and Sarau HM (1995) Time-r
elated changes in myeloperoxidase activity and leukotriene B_Four receptor b
inding reflect leukocyte influx in cerebral focal stroke.Mol Chem Neuro pathol  24: 13-30; Wang XK, Barone FC, Aiyar NV, Feuerstein GZ (1997) Inc.
reased interleukin-1 receptor and interleukin-1 receptor antagonist gene
 expression after focal stroke.Stroke 28: 155-162). Cortical sample immediately
It was frozen in liquid nitrogen and stored at -80 ° C.

Northern Hybridization Analysis: When preparing RNA, cortical samples were homogenized in guanidinium thiocyanate solution and extracted with phenol and chloroform as previously described (Chomczynski P, Sacchi N (1987) Sing.
le-step method of RNA isolation by acid guanidinum thiocyanate-phenol-ch
loroform extraction. Anal Biochem 162: 156-159; Wang XK, Siren AL, Liu
Y, Yue TL, Barone FC, Feuerstein GZ (1994) Upregulation of intercellula
r adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells
in rat ischemic cortex. Mol Brain Res 26: 61-68). RNA sample (40μ
(g / lane) was electrophoresed through a formaldehyde-agarose slab gel and transferred to a GeneScreen Plus membrane (DuPont-New England Nuclear). For Northern blot analysis, OPN or ribosomal protein L32 cDNA was prepared as previously described (Wang XK, Louden C, Ohlstein EH, Stadel JM, Gu.
JL, Yue TL (1996) Osteopontin expression in platelet-derived growth fac
tor-stimulated vascular smooth muscle cells and carotid artery after bal
. loon angioplasty Aterioscler Thromb Vasc Biol 16 : 1365-1372), further random - primed DNA labeling Kid (using ^{Boehringer Mannheim) [α- 3 2 P} ] dATP (3000Ci / mmol, uniformly labeled with Amersham Corp) did. 5 × SSPE (750 mM NaCl, 50 mM NaH ₂ PO ₄ , pH 7.
6, 5 mM EDTA), 50% formamide, 5 × Denhardt's solution, 2% SD
S, 100 μg / ml poly A and 200 μg / mg in boiled salmon semen DNA,
Hybridization of each probe was performed overnight at 42 ° C. with 1 × 10 ⁶ cpm / ml of probe. Change the membrane every 30 minutes, at 2 ° C at 65 ° C
It was washed with SSPE and 2% SDS for 1 to 2 hours and then autoradiographed at -70 ° C using a Cronex Lightning-Plus intensifying screen at various times depending on the signal intensity. The intensity of the relevant band was measured using the PhosphorImager of the ImageQuant software package (Molecular Dynamics).
The probe is 10 mM Tris, pH 7.5, 1 mM EDTA, pH 8.0, 1.
Stripped from the membrane in 95% SDS for 20 minutes at 95 ° C., then 1 × with 2 × SSPE.
It was washed for 0 minutes and then hybridized again with other probes. r
Expression of the pL32 gene was relatively constant under these experimental conditions (Wang XK,
Siren AL, Liu Y, Yue TL, Barone FC, Feuerstein GZ (1994) Upregulation
of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular end
othelial cells in rat ischemic cortex. Mol Brain Res 26: 61-68; Wang XK
, Yue TL, Barone FR, White RF, Feuerstein GZ (1994) Concomitant cortica
l expression of TNF-α and IL-1β mRNAs follows early response gene expr
Mol Chem Neuropathol 23: 103-114), and is therefore used to normalize the differences between loaded samples in each lane.

In situ hybridization: Tissue preparation, in vitro transcription and complex in situ hybridization, and immunohistochemistry have been previously described (Ellison JA, Scully SA, de Vellis J (1996) Evidence for neuronal.
regulation of oligodendrocyte development: cellular localization of pla
telet-derived growth factor a receptor and A-chain mRNA during rat cereb
Ral cortex development. J Neurosci Res 45: 28-39) Performed with minor modifications to the description of the in situ hybridization protocol. Tissue fragment (1
2 μm) was incubated with ED1 antibody (Biosource International) at 4 ° C. overnight. Antibodies were detected using the Vector Labs ABC kit using diaminobenzidine as the substrate and according to the manufacturer's instructions. Immediately after antibody detection, tissues were deproteinized in 0.2 M HCl and then acetylated with 0.1 M triethanolamine (pH 8) containing 0.25% acetic anhydride. OPN probe (1 × 10 ⁶ cpm / m) labeled with antisense or sense [ ³³ P] UTP
1) was applied to the tissues and hybridized overnight at 60 ° C. Post-hybridization washes were modified as follows: 2 × SSC for 10 minutes at 50 ° C .; 20 μg / ml RNase for 30 minutes at 37 ° C .; 2 × SSC for 5 minutes at room temperature.
1 × SSC, 0.5 × SSC; 0.1 × SSC at 55 ° C. for 20 minutes; 0.1 × SSC at room temperature for 5 minutes. The pieces are dehydrated and dried, and Hyperfilm Betamax (
Hyperfilm βmax) (Amersham) was exposed overnight. In the case of emulsions, autoradiographic sections were immersed in NTB2 emulsion (Kodak) and exposed at 4 ° C for 7 days.

Immunohistochemistry: For immunohistochemistry studies, rats were treated with chronic MCAO 6,12.
And killed at 24 hours, and at 5, 10 and 15 days. After systemic perfusion with 10% phosphate buffered formalin, brains were removed from 3 rats (n = 3) at each time point and stored in formalin for 24 hours, after which the sample was transferred to 70% ethanol. Standard histological procedures were performed using a Vacuum Infiltration Processor (Miles). After embedding in paraffin, 5 μm fragments were cut, stained with hematoxylin and eosin, and evaluated by microscopic observation. Further fragments will be immunohistochemically evaluated for OPN, ED-1 (mononuclear cell / macrophage marker), glial fibrillary acidic protein (GFAP; a marker for activated glia) and S-100 (neurofilament marker) expression. For Capillary Gap Plus Microscope Slides (Bio
Tek). Immunohistochemistry was performed using mouse anti-rat OPN antibody, MPIIIB10 (Dev).
elopmental Studies Hybridoma Bank, University of Iowa, Iowa City, IA; 1: 5
0 dilution), monoclonal anti-ED1 (Harlan Bioproducts for Science; 1: 100
Dilution), rabbit anti-bovine GFAP (DAKO; 1: 750 or 1: 20,000 dilution) and rabbit anti-bovine S100 (DAKO; 1: 20,000 dilution) and performed as previously described. (Wang XK, Louden C, Ohlstein EH, Stadel JM, Gu JL, Yue TL (1
996) Osteopontin expression in platelet-derived growth factor-stimulated
vascular smooth muscle cells and carotid artery after balloon angioplas
ty. Aterioscler Thromb Vasc Biol 16: 1365-1372).

Cell culture and migration assay: Rat C6 glial cells (ATCC CCL107) were assayed in American
Obtained from Type Cultured Collection (ATCC), Dulbecco's modified Eagle's medium (DMEM) (GIB) supplemented with 5% fetal bovine serum
Cultured in CO BRL). Normal human astrocytes purchased from Clonetics, 5
Astrocytes containing% fetal bovine serum, 20 ng / ml hEGF, 25 microgram / ml insulin, 25 ng / ml progesterone, 50 microgram / ml transferin, 50 microgram / ml gentamicin and 50 ng / ml amphotericin-B. It was cultured in a basic medium (Clonetics). The human astrocytes were subcultured according to the manufacturer's instructions and cell migration assay was performed before subculture 3.

Cell migration assays were performed as previously reported (Hidaka YT, Eda T, Yonemot.
o M, Kamei T (1992) Inhibition of cultured vascular smooth muscle cell m
igration by simvastatin (MK-7333) Atherosclerosis 95: 87-94) using a polycarbonate membrane with 8 micrometer pores (Costar) in a transwell cell culture chamber. The underside of the membrane was pre-coated with different concentrations of recombinant rat OPN (Yue TL, McKenna PJ, Ohlstein EH, Farach-Carson MC, Butler W.
T, Johanson K, McDevitt P, Feuerstein GZ, Stadel JM (1994) Osteopontin-s
timulated vascular smooth muscle cell migration is mediated by β3 integ
rin. Exp Cell Res 214: 459-464). C6 cells in DMEM and 0 human astrocytes
． The cells were suspended and resuspended in astrocyte basal medium supplemented with 2% bovine serum albumin at a concentration of 3 × 10 ⁶ and 2 × 10 ⁵ cells / mL, respectively. As a standard assay, 0.2 ml of cell suspension was placed in the upper compartment of the chamber before use and the lower compartment was supplemented with 0.6 ml of DMEM or 0.2% bovine serum albumin astrocyte base. Medium was included. Incubation was for 24 hours at 37 ° C. in 5% CO ₂ . After the incubation, non-migrated cells on the upper surface were gently peeled off, the filter was fixed in methanol and stained with 10% Giemsa stain. The number of cells that migrated to the lower surface of the filter was measured by optical density at 640 nm (C6 cells) or counted in 4 high power fields (x100) per filter (Hidaka YT, Eda T, Yonemoto M, Kamei T ( 1992) Inhibi
tion of cultured vascular smooth muscle cell migration by simvastatin (M
K-7333). Atherosclerosis 95: 87-94; Yue TL, McKenna PJ, Ohlstein EH, Far.
ach-Carson MC, Butler WT, Johanson K, McDevitt P, Feuerstein GZ, Stadel
JM (1994) Osteopontin-stimulated vascular smooth muscle cell migration i
s mediated by β3 integrin. Exp Cell Res 214: 459-464). The relative number of cells measured by optical density was evaluated parallel to the cell count by microscopy to determine the percentage of migrated cells. The experiment was performed in triplicate.

The present invention is not limited to the specific embodiments described above, but the rights are retained in the specific embodiments listed, and all modifications described herein are within the scope of the claims. It is a part. Various references for publications, patents and other publications cited herein, including the state of the art, are incorporated herein by reference in their entirety.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 401/12 C07D 401/12 // A61P 43/00 A61P 43/00 C07D 471/04 114 C07D 471/04 114Z (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AU, BA, BB, BG, BR , BZ, CA, CN, CZ, DZ, EE, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV, MA, MG, MK, MN, MX, MZ, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, TZ, UA, US, UZ, VN, YU, ZA (72) Inventor Yue・ Tian-ri United States 19083 Arlington Road, No.308, F-Term, Arlington Road, Havertown, Pennsylvania (Reference) 4C063 AA01 BB08 CC19 DD12 EE01 4C065 AA04 BB09 CC01 DD02 EE02 HH01 JJ01 KK04 PP03 4C084 AA17 ZA01 ZA89 ZC42 MA04A0A14 ZA01 ZA89 ZC42

Claims (10)

[Claims] 1. A method of treating stroke, comprising administering an effective amount of a vitronectin receptor antagonist to a subject in need thereof. 2. The vitronectin receptor has the formula (I): [Chemical 1] [In the formula:   R¹Is R⁷Or AC_0-4Alkyl, AC_2-4Alkynyl, AC _2-4 Alkynyl, AC_3-4Oxoalkynyl, AC_3-4Oxo Archi
Nil, AC_1-4Aminoalkyl, AC_3-4Aminoalkynyl, AC_{Three -4} Aminoalkynyl, which are R¹⁰Or R⁷One or more of
May be replaced by all permissible combinations of   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mO
R ', -S (O)_mNR'R ", -PO (OR '), -PO (OR')_Two, -N
O_TwoOr tetrazolyl;   Each R⁸Are independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'
OR 'or -OCR'_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C
(O) R ', C (O) NR'_TwoOr -CO_TwoR ';   R¹⁰Is H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -C
F_Three, CF_ThreeS (O)_r-, -CO_TwoR ', -CONR'_Two, A-C_0-6Al
Kill-, AC_1-6Oxoalkyl-, AC_2-6Alkenyl, AC_{2- 6} Alkynyl, AC_0-6Alkyloxy-, AC_0-6Alkylamino-
Or AC_0-6Alkyl-S (O)_r-Is;   R¹¹Is R ', -C (O) R', -C (O) NR '._Two, -C (O) OR ',
-S (O)_mR'or -S (O)_mNR '_TwoAnd   R^TwoIs [Chemical 2]   W is-(CHR^g)_a-U- (CHR^g)_b-Is;   U does not exist, or CO, CR^g _Two, C (= CR^g _Two), S (O)_k , O, NR^g, CR^gOR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(O
R^k), C (O) CR^g _Two, CR^g _TwoC (O), CONRⁱ, NRⁱCO, OC
(O), C (O) O, C (S) O, OC (S), C (S) NR^g, NR^gC (S
), S (O)_TwoNR^g, NR^gS (O)_TwoN = N, NR^gNR^g, NR^gCR^g _Two , CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gso
Yes;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cyclo
Alkyl-C_0-6Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fAnd   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cyclo
Alkyl-C_0-6Alkyl, Ar-C_0-6Alkyl or halogen, CN,
NR^g _Two, OR^g, SR^g, CO_TwoR^g, And CON (R^g)_TwoSelected from
C substituted by 1 to 3 groups_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6 Alkyl, C_3-7Cycloalkyl-C_0-6Alkyl or (CH_Two)_kCO _Two R^gAnd   R^bAnd R^cIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het
-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen
CF_Three, OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_2,CO
(NR^f)_Two, CH_TwoN (R^f)_TwoIndependently selected from or R^bAnd
And R^cAre taken together to form a 5- or 6-membered aromatic or non-aromatic carbon or heterocycle
To form halogen, CF_Three, C_1-4Alkyl, OR^f, S (O)_kR ^f , COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_2,CO (NR^f)_TwoOh
And CH_TwoN (R^f)_TwoMay be substituted with up to 3 substituents selected from:
Or forming methylenedioxy;   Q¹, Q^Two, Q^ThreeAnd Q^FourAre independently N or CR^yHowever;
, Q¹, Q^Two, Q^ThreeAnd Q^FourAt most one is N;   R'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Shiku
Lower alkyl-C_0-6Alkyl;   R "is R ', -C (O) R' or -C (O) OR ';   R '' 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-
6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three,
OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_2,CO (NR^f)_Two , CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two,
-CF_Three, CF_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _Two Or halo, -OR^g, -SR^g, -CN, -NR^gR ", -NO_Two, -C
F_Three, R'S (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoBy
C which may be replaced by_1-6Alkyl;   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2;   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1; and   v is 0 or 1.] A compound represented by: or a pharmaceutically acceptable salt thereof.
the method of. 3. The vitronectin receptor antagonist is (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (
2,2,2-Trifluoroethyl) -2,3,4,5-tetrahydro-1H-2
-The method according to claim 1, which is benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. 4. A vitronectin receptor antagonist is (S) -8- [2
-[6- (Methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-
The method according to claim 1, which is 1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. 5. A vitronectin receptor antagonist is (S) -10,1.
1-dihydro-3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid or The method according to claim 1, which is a pharmaceutically acceptable salt thereof. 6. Use of a vitronectin receptor antagonist in the manufacture of a medicament for the treatment of stroke. 7. A vitronectin receptor antagonist has the formula (I): [Chemical 3] [In the formula:   R¹Is R⁷Or AC_0-4Alkyl, AC_2-4Alkynyl, AC _2-4 Alkynyl, AC_3-4Oxoalkynyl, AC_3-4Oxo Archi
Nil, AC_1-4Aminoalkyl, AC_3-4Aminoalkynyl, AC_{Three -4} Aminoalkynyl, which are R¹⁰Or R⁷One or more of
May be replaced by all permissible combinations of   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mO
R ', -S (O)_mNR'R ", -PO (OR '), -PO (OR')_Two, -N
O_TwoOr tetrazolyl;   Each R⁸Are independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'
OR 'or -OCR'_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C
(O) R ', C (O) NR'_TwoOr -CO_TwoR ';   R¹⁰Is H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -C
F_Three, CF_ThreeS (O)_r-, -CO_TwoR ', -CONR'_Two, A-C_0-6Al
Kill-, AC_1-6Oxoalkyl-, AC_2-6Alkenyl, AC_{2- 6} Alkynyl, AC_0-6Alkyloxy-, AC_0-6Alkylamino-
Or AC_0-6Alkyl-S (O)_r-Is;   R¹¹Is R ', -C (O) R', -C (O) NR '._Two, -C (O) OR ',
-S (O)_mR'or -S (O)_mNR '_TwoAnd   R^TwoIs [Chemical 4]   W is-(CHR^g)_a-U- (CHR^g)_b-Is;   U does not exist, or CO, CR^g _Two, C (= CR^g _Two), S (O)_k , O, NR^g, CR^gOR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(O
R^k), C (O) CR^g _Two, CR^g _TwoC (O), CONRⁱ, NRⁱCO, OC
(O), C (O) O, C (S) O, OC (S), C (S) NR^g, NR^gC (S
), S (O)_TwoNR^g, NR^gS (O)_TwoN = N, NR^gNR^g, NR^gCR^g _Two , CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gso
Yes;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cyclo
Alkyl-C_0-6Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fAnd   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cyclo
Alkyl-C_0-6Alkyl, Ar-C_0-6Alkyl or halogen, CN,
NR^g _Two, OR^g, SR^g, CO_TwoR^g, And CON (R^g)_TwoSelected from
C substituted by 1 to 3 groups_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6 Alkyl, C_3-7Cycloalkyl-C_0-6Alkyl or (CH_Two)_kCO _Two R^gAnd   R^bAnd R^cIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het
-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen
CF_Three, OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_2,CO
(NR^f)_Two, CH_TwoN (R^f)_TwoIndependently selected from or R^bAnd
And R^cAre taken together to form a 5- or 6-membered aromatic or non-aromatic carbon or heterocycle
To form halogen, CF_Three, C_1-4Alkyl, OR^f, S (O)_kR ^f , COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_2,CO (NR^f)_TwoOh
And CH_TwoN (R^f)_TwoMay be substituted with up to 3 substituents selected from:
Or forming methylenedioxy;   Q¹, Q^Two, Q^ThreeAnd Q^FourAre independently N or CR^yHowever;
, Q¹, Q^Two, Q^ThreeAnd Q^FourAt most one is N;   R'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Shiku
Lower alkyl-C_0-6Alkyl;   R "is R ', -C (O) R' or -C (O) OR ';   R '' 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-
6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three,
OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_2,CO (NR^f)_Two , CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two,
-CF_Three, CF_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _Two Or halo, -OR^g, -SR^g, -CN, -NR^gR ", -NO_Two, -C
F_Three, R'S (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoBy
C which may be replaced by_1-6Alkyl;   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2;   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1; and   v is 0 or 1.] 7. The compound represented by: or a pharmaceutically acceptable salt thereof.
Use of. 8. The vitronectin receptor antagonist is (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (
2,2,2-Trifluoroethyl) -2,3,4,5-tetrahydro-1H-2
Use according to claim 6, which is-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. 9. A vitronectin receptor antagonist is (S) -8- [2
-[6- (Methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-
The use according to claim 6, which is 1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. 10. A vitronectin receptor antagonist is (S) -10,
11-dihydro-3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid or The use according to claim 6, which is a pharmaceutically acceptable salt thereof.