CN1223637A - Phenylalamine derivatives as integrin inhibitors - Google Patents
Phenylalamine derivatives as integrin inhibitors Download PDFInfo
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- CN1223637A CN1223637A CN97195896A CN97195896A CN1223637A CN 1223637 A CN1223637 A CN 1223637A CN 97195896 A CN97195896 A CN 97195896A CN 97195896 A CN97195896 A CN 97195896A CN 1223637 A CN1223637 A CN 1223637A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Compounds of formula (I) wherein X, Y, Z, R[1], R[2], R[3] and R[4] have the meaning stated in claim 1, with the proviso that at least one element chosen from the group X, Y, Z must be CH2, as well as their physiologically harmless salts, can be used as integrin inhibitors, particularly for prophylaxis and treatment of circulatory diseases, in case of thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, osteoporosis, in pathological processes which are maintained or propagated by angiogenesis, and in tumor therapy.
Description
The present invention relates to the compound of formula I
Wherein X does not exist, or has the alkylidene group of 4-8 carbon atom, arylidene, inferior cycloalkanes
Base, or have 1-3 N, O and/or S atom, unsubstituted or by A,
Oxo and/or R
4Replace once, the assorted cycloalkylidene of twice or three times, Y and Z are not exist in all cases independently, or alkylidene group, O, S, NH,
C (=O), and CONH, NHCO, C (=S), SO
2NH, CA=CA ' or
-C ≡ C-, R
1Be H
2N-C (=NH) or H
2N (C=NH)-NH, wherein primary amine groups can also be provided
Conventional amino protecting group or can be by A, Ar or R
5Replace once, twice or three
Inferior, R
2Be A, Ar or inferior aralkyl, R
3Be H or A, R
4Be H, Hal, OA, NHA, NAA ', CN, NO
2, SA,
SOA, SO
2A, SO
2Ar or SO
3H, R
5Be alkanoyl or loop chain alkyloyl with 1-18 carbon atom, one of them,
Two or three methylene radical can be by N, and O and/or S replace,
Ar-CO-or Ar-alkylidene group-CO-, A and A ' in all cases independently, be H or alkyl with 1～15 carbon atom or
Cycloalkyl, it is unsubstituted or by R
4Replace once, twice or three times and wherein
One, two, three methylene radical can be by N, and O and/or S replace, and Ar is monokaryon or the double-core with 0,1,2,3 or 4 N, O and/or S atom
Aromatic ring, it is unsubstituted or by A and/or R
4Replace once, twice or three times, Hal is F, Cl, Br or I, precondition is that at least one primitive that is selected from radicals X, Y and Z must be CH
2And harmless salt on its physiology.
Similar compounds is for example from EP0478363, and EP0478328 is known among WO94/12181 and the WO95/32710.
The objective of the invention is to find valuable novel cpd, especially can be used in the compound of medicine.
Have now found that the compound of formula I and their salt have the very active and while better tolerance of valuable pharmacological.Especially, they can be used as integrin inhibitor, and meanwhile they also suppress α
vThe interaction of integrin receptor and part.This compound is for beta 2 integrin alpha
vβ
3And α
vβ
5Demonstrate special activity.This compound is as Vitronectic receptor α
vβ
3Adhesion receptor antagonists have extra high activity.For example by using people such as J.W.Smith at J.Biol.Chem.265, the method for describing among 11008-11013 and the 12267-12271 (1990) illustrates this effect.
The ability that some representative compounds inhibition vitronectin of formula I are incorporated into acceptor has obtained proof experimentally.Pharmacological test data is listed in the table I.
At Curr.Opin.Cell.Biol.5,864 (1993), B.Felding-Habermann and DA.Cheresh described integrin as adhesion receptor for various symptom or syndromes, especially for Vitronectic receptor α
vβ
3Importance.
By P.C.Brooks, R.A.Clark and D.A.Cheresh are described in science (Science) 264569-71 (1994) to the interactional dependency between blood vessel integrin and extracellular matrix proteins in the generation of blood vessel.
Use the cyclic peptide to suppress this interaction and therefore caused vasculogenesis with the possibility of the apoptosis of vascular cell by P.C.Brooks, A.M.Montgomery, M.Rosenfeld, R.A.Reisfeld, T.-Hu, G.Klier and D.A.Cheresh be at cell (Cell), and 79,1157-64 reports in (1994).
This novel cpd prevents that also viable cell from adhering to corresponding stroma protein and prevent also that therefore tumor cell adhesion from can obtain in the experimental evidence on the stroma protein in the cell adhesion test, this test is according to people such as F.Mitjans, J.Cell Science 108, similar method is carried out among the 2825-2838 (1995).
At J.Clin.Invest.96, among the 1815-1822 (1995), people such as P.C.Brooks have described the α of control cancer and treatment tumor promotion vascular disease
vβ
3Antagonist.Therefore the novel cpd of formula I can be used as pharmaceutical active compounds, is particularly useful for treating the vascular disease of tumor promotion.So the novel cpd of formula I can be used as pharmaceutical active compounds, is particularly useful for treating tumor disease, osteoporosis and osteolysis disease, and be used to suppress vasculogenesis.
Blocking-up integrin receptor and part, the fibrinogenic part of (sci) fibrinogen deceptor (glycoprotein) for example, interactional generalformula can prevent the diffusion of the tumour cell that causes because of transfer as GP II b/ III a antagonist.This can be proved by following observations.
Owing to tumour cell and hematoblastic interaction have formed miniature coacervate (small thrombus), tumour cell is diffused in the vascular system from local tumor.Tumour cell is protected in miniature coacervate and is protected and can not discerned by immune cell.Miniature coacervate can adhere to cell walls, further penetrates in the tissue thereby help tumour cell.Because the formation of small thrombus is to be incorporated into media on the scleroproein acceptor on the active thrombocyte by scleroproein, GP II a/ III b antagonist can be considered to effective transfer inhibitor.
Be incorporated into hematoblastic fibrinogen deceptor in order to suppress Fibrinogen, fibronectin and von willebrand's factor, the compound of formula I also suppresses on the surface that other adhesivity protein such as vitronectin, collagen and laminine be incorporated into different cell types on the corresponding acceptor.They especially prevent the formation of the small thrombus of thrombocyte and therefore can be used in treatment thrombus, shock, myocardial infarction, inflammation and atherosclerosis.
The performance of this compound can also illustrate by using the method for describing among the EP-A1-0462960.Fibrinogen and fibrinogen deceptor bonded suppress and can be illustrated by the method for describing among the EP-A1-0381033.
This novel cpd also barrier suppresses Fibrinogen to be incorporated into this experimental fact on the corresponding acceptor is that some representative compounds for formula I are confirmed by experiment.Pharmacological experimental data is listed in the table II.
The effect that suppresses the thrombocyte reunion can be illustrated by the method for in vitro using Born (nature, 4832,927-929,1962).
So, the present invention relates to compound with formula I according to claim 1, and/or harmless salt on their pharmacology, can be used for preparing medicine as integrin inhibitor.The invention particularly relates to according to claim 1, R wherein
2Be the generalformula of camphor-10-base, and/or their harmless salt, can be used for preparing the medicine of on pathology, controlling vascular disease, tumour, osteoporosis, inflammation and infection.
The compound of formula I, as the pharmaceutical active compounds in medical treatment and the veterinary applications, be used to prevent and/or treat thrombus, myocardial infarction, atherosclerosis, inflammation, shock, stenocardia, tumor disease, osteolysis disease such as osteoporosis, pathologic vessels disease such as inflammation, eye illness, diabetic retinopathy, macular degeneration, myopia, the eye reticuloendothelial cytomycosis, rheumatoid arthritis, osteoarthritis, RI glaucoma, ulcerative colitis, Crohn disease, atherosclerosis, psoriasis, postangioplasty restenosis, virus infection, infectation of bacteria, fungi infestation, acute recial disease and wound healing are to support healing process.
The compound of formula I can be used as biocide in the operation of using biomaterial, implant, conduit or schrittmacher.In context, they have antibiotic preservative effect.Antimicrobial acivity can infected and immunity by people such as P.Valentin-Weigund, and the method for describing among the 2851-2855 (1988) illustrates.
The invention further relates to the method for preparation according to the generalformula and its esters of claim 1, the method is characterized in that: a) by discharging the compound of formula I from this derivative with the functional derivative of solvation reagent or hydrogenolysis agent treated generalformula, or b) compound of general formula II
R wherein
1, R
3, R
4, X, Y and Z have meaning same in the claim 1, with the compound reaction of general formula III
R
2-SO
2-L III is R wherein
2Having same meaning of claim 1 and L is Cl, Br, I, OH or esterified after the OH group that can participate in reacting, or c) ester of formula I is hydrolyzed, or d) radicals R
1And/or R
3Be converted to another kind of radicals R
1And/or R
3, and/or e) alkalescence of formula I or acidic cpd be by being converted to its a kind of salt with acid or alkaline purification.
The compound of formula I has at least one chiral centre and can exist with several stereoisomeric forms in any ratio.All these forms (for example D and L shaped formula) and their mixture (for example DL form) are included in the formula I.
So-called prodrug derivant, promptly with for example alkyl or acyl group, carbohydrate or oligopeptide in addition modification and in microbe fast division form the generalformula of active new compound, be also included within the novel cpd.
Abbreviation listed above and abbreviation hereinafter have following meaning: Ac ethanoyl uncle BOC-butoxy carbonyl CBZ or Z benzyloxycarbonyl DCCl dicyclohexyl carbodiimide DMF methylformamide EDCl N-ethyl-N; N '-(dimethylaminopropyl) carbodiimide Et ethyl Fmoc 9-fluorenyl methoxy carbonyl HOBT I-hydroxybenzotriazole Me methyl Mtr 4-methoxyl group-2; 3,6-trimethylphenyl alkylsulfonyl HONSu N-hydroxy-succinamide OBut tertiary butyl ester Oct capryloyl OMe methyl ester OEt ethyl ester POA phenoxy group ethanoyl TFA trifluoroacetic acid Trt trityl group.
For whole inventions, all groups several times appear, can be identical or different as A and A ', that is, be independent of each other.
In above general formula, alkyl is methyl preferably, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the second month in a season-butyl or the tertiary butyl and can be amyl group, l-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2, the 2-dimethyl propyl, 1-ethyl propyl, hexyl, l-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3, the 3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group, heptyl, octyl group, nonyl or decyl.
Cycloalkyl is cyclopropyl preferably, cyclobutyl, and cyclopentyl [sic], cyclohexyl, suberyl or 3-methyl, cycloalkyl is the group of bicyclic terpene preferably; Camphor-10-base is particularly preferred.
Alkylidene group is methylene radical preferably, ethylidene, and propylidene, butylidene, or pentylidene, and hexylidene, inferior heptyl, octylene, nonamethylene or inferior decyl.Inferior aralkyl is alkylidene group phenyl and for example preferred benzyl or styroyl preferably.
Cycloalkylidene is cyclopropylidene preferably, and 1,2-or 1, the inferior cyclobutyl of 3-, 1,2-or 1,3-cyclopentylidene or 1,2-, 1,3-or 1,4-cyclohexylidene and 1,2-, 1,3-or 1,4 inferior suberyl.
Alkanoyl is formyl radical preferably, ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl; oenanthyl, capryloyl, nonanoyl, decanoyl, undecanoyl, lauroyl; tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecane acyl group or octadecanoyl.
Alkyl, alkylidene group, cycloalkyl, cycloalkylidene, the preferred substituents of alkanoyl and loop chain alkyloyl is, for example, Hal, OA, NHA, NAA ', CN, NO
2, SA, SOA, SO
2A, SO
2Ar and/or SO
3H especially for example is F, Cl, hydroxyl, methoxyl group, oxyethyl group, amino, dimethylamino, methyl sulfenyl, methylsulfinyl, methyl sulphonyl or phenyl-alkylsulfonyl.
The preferred substituents of Ar and arylidene is, for example, and A and/or Hal, OA, NHA, NAA ', CN, NO
2, SA, SOA, SO
2A, SO
2Ar and/or SO
3H especially for example is F, Cl, hydroxyl, methoxyl group, oxyethyl group, amino, dimethylamino, methyl sulfenyl, methylsulfinyl, methyl sulphonyl or phenyl sulfonyl.
At alkyl, alkylidene group, cycloalkyl, ring-alkylidene group, in alkanoyl and the loop chain alkyloyl, in each case, one, two or three methylene radical can be by N, and O and/or S replace.
Ar-CO is aroyl and preferably benzoyl or naphthoyl.
Ar is unsubstituted, and is preferred, as specified monosubstituted phenyl, is phenyl preferably and especially; o-, m-or p-tolyl, o-, m-or p-ethylphenyl; o-, m-or p-propyl group phenyl, o-, m-or p-isopropyl phenyl; o-, m-or p-tert-butyl-phenyl, o-, m-or p-cyano-phenyl; o-, m-or p-p-methoxy-phenyl, o-; m-or p-ethoxyl phenenyl, o-, m-or p-fluorophenyl; o-, m-or p-bromophenyl, o-; m-or p-chloro-phenyl-, o-, m-or p-methyl sulfenyl phenyl; o-, m-or p-methylsulfinyl phenyl, o-; m-or p-methyl sulphonyl phenyl, o-, m-or p-aminophenyl; o-, m-or p-methylamino phenyl, o-; m-or p-dimethylaminophenyl or o-, m-or p-nitrophenyl and same preferred; 2,3-, 2; 4-, 2,5-; 2,6-, 3; 4-or 3,5-difluorophenyl, 2; 3-, 2,4-; 2,5-, 2; 6-, 3,4-or 3; the 5-dichlorophenyl, 2,3-; 2,4-, 2; 5-, 2,6-; 3,4-or 3,5-dibromo phenyl; 2-chloro-3-methyl-, 2-chloro-4 methyl-, 2-chloro-5-methyl-; 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-; the 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-; 3 chloro-5-methyl-or 3-methyl-4-chloro-phenyl-, 2-bromo-3 methyl-, 2-bromo-4-methyl-; 2-bromo-5-methyl-, 2-bromine 6-methyl-, 2-methyl-3-bromo-; 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-; 3-bromo-4-methyl-, 3-bromo-5-methyl-or 3-methyl-4-bromophenyl, 2; 4-or 2,5-dinitrophenyl, 2; 5-or 3,4-Dimethoxyphenyl, 2; 3,4-, 2; 3,5-, 2; 3,6-, 2; 4,6-or 3,4; the 5-trichlorophenyl, 2,4; 6-tri-tert phenyl, 2,5-two-aminomethyl phenyl; the p-iodophenyl, 4-fluoro-3-chloro-phenyl-, 4-fluoro-3; the 5-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2; 5-two fluoro-4-bromophenyls, 2,4-two chloro-5-aminomethyl phenyls; 3-bromo-6-p-methoxy-phenyl, 3-chloro-6-p-methoxy-phenyl, 2-methoxyl group-5-aminomethyl phenyl; 2,4,6-triisopropyl phenyl; naphthyl, 1,3-benzo dioxo-5-base; 1,4-benzodioxan-6-base, diazosulfide-5-base or or Ben Bing oxadiazole-5-base.
In addition, Ar is 2-or 3-furyl preferably, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 37 or 4-pyridyl or 2-, 4-, 5-or 6-pyrimidyl and same preferred, 1,2,3-triazole-1-,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 1,2,3-oxadiazole-4-or-the 5-base, 1,2,4-oxadiazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,2,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 2-, 3-, 4-, 5-or 6-2H-thiapyran base, 2-, 3-or 4-4-H-thiapyran base [sic], 3 or the 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-benzo thienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, l-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzoisoxazole base, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 4-, 5-, 6-or 7-benzene-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl or 2-, 4-, 5-, 6-, 7-or 8-quinazolyl.
Arylidene have with among the Ar given identical meaning, precondition is that other key of aromatic systems is connected in the adjacent base of nearest keyed jointing (bonding neighbour).
Assorted cycloalkylidene preferably 1,2-, 2,3-or 1,3-pyrrolidyl, 1,2-, 2,4-, 4,5-or 1,5-imidazolidyl, 1,2-, 2,3-or 1, the 3-pyrazolidyl, 2,3-, 3,4-, 4,5-or 2,5-oxazolidinyl, 1,2-, 2,3-, 3,4-or or 1,4-isoxazole alkyl, 2,3-, 3,4-, 4,5-or 2,5-thiazolidyl, 2,3-, 3,4-, 4,5-or 2,5-isothiazole alkyl, 1,2-, 2,3-, 3,4-or 1,4-piperidyl, 1,4-or 1,2-piperazinyl and same preferred, 1,2,3-tetrahydrochysene triazole-1,2-or-1,4-base, 1,2,4-tetrahydrochysene triazole-1,2-or-3,5-base, 1,2-or 2,5-tetrahydrochysene tetrazyl, 1,2,3-Si Qing oxadiazole-2,3-,-3,4-,-4,5-or-1,5-base, 1,2,4-Si Qing oxadiazole-2,3-,-3,4-or-4,5-base, 1,3,4-thiodiazolidine-2,3-,-3,4-,-4,5-or-1,5-base, 1,2,4-thiodiazolidine-2,3-,-3,4-,-4,5-or-1,5-base, 1,2,3-thiadiazoles-2,3-,-3,4-,-4,5-or-1,5-base.2,3-or 3,4-morpholine subbase or 2,3-, 3,4-or 2,4-thio-morpholinyl.
The amido protecting group is ethanoyl preferably, propionyl, butyryl radicals; phenyl acetyl, benzoyl, toluyl; POA, methoxycarbonyl, ethoxy carbonyl; 2,2,2-three chloro-ethoxy carbonyls; BOC, 2-iodine ethoxy carbonyl, CBZ (＂ carbonyl phenoxy group ＂); 4-methoxyl group benzyloxy base carbonyl, FMOC, Mtr or benzyl.
Correspondingly, The present invention be more particularly directed to those compounds of formula I, wherein at least one has an above-mentioned preferred meaning in this group.The preferred group of some of these compounds can be by the expressing and wherein do not have more accurate specified group to have meaning in the formula I with lower section formula I a-I e of corresponding formula I, but R in a) wherein
1Be H
2N-C (=NH)
X is the alkylidene group with 1-6 carbon atom,
Y is O,
R
2Be A,
R
3And R
4Be H; At b) in R
1Be H
2N-(C=NH)-NH,
X is the alkylidene group with 1-6 carbon atom,
Y is O,
R
2Be A,
R
3And R
4Be H; At c) in X be alkylidene group with 1-6 carbon atom,
There is not Y
R
3And R
4Be H and
R
2Be that aryl is at d) in R
1Be H
2N-(C=NH)-NH,
X is the alkylidene group with 1-6 carbon atom,
Y is CONH,
R
3And R
4Be H and
R
2Be that A is at e) in X be alkylidene group with 1-6 carbon atom,
Y is O or CO-NH,
There is not Z
R
2It is camphor-10-base
R
3Be H or A and
R
4Be N
The compound of formula I, with their initial compounds of preparation, can prepare (for example at classic such as Houben-Weyl according to known method own with according to the method described in the document in addition, Methoden der organischen Chemie (organic chemistry method), Georg-Thieme-Verlag, Stuttgart), by using the reaction conditions of known and suitable this reaction.In context, also can use itself the known but version do not mentioned in detail here.
If desired, initial compounds also can form on the spot, and they do not need to separate from reaction mixture and just are used for the compound that next step reaction forms formula I immediately like this.
The compound of formula I preferably obtains by a kind of compound that discharges formula I from their functional derivative, and method is with solvation or this derivative of hydrogenolysis agent treated.
Preferred initial compounds is those of general molecular formula I for solvation or hydrogenolysis; just; replace one or more free amine groups and/or hydroxyl; they contain corresponding; protected amino and/or hydroxyl; preferably carry amino protecting group rather than be connected in those initial compounds of the H atom of N atom; especially carry those initial compounds of R '-N group; wherein R ' is an amino protecting group; rather than NH base; and/or carry those initial compounds of the H atom of hydroxyl protecting group rather than hydroxyl; for example those initial compounds of corresponding formula I, wherein R " be hydroxyl protecting group rather than-the COOH base.
Several-identical or different-protected amino and/or hydroxyl also are present in the molecule of initial compounds.If existing protecting group is different mutually, can selectivity eliminate in many cases.
To express phrase " amino protecting group " generally be known and be meant the group that is fit to that protection (sealing) amino makes it chemical reaction does not take place but carries out in other position of molecule removing easily behind the required chemical reaction.Do not replace or substituted acyl group, aryl, aralkoxy methyl or the aralkyl typical case of this type of group especially.Owing to remove amino protecting group after required reaction (or reaction sequence), their character and size are not crucial; Yet, have 1-20, especially those of 1-8 carbon atom are preferred.For method of the present invention, express phrase " acyl group " and should on the wideest meaning, understand.It comprises from aliphatic series, araliphatic, aromatics or heterocyclic carboxylic acid or sulfonic acid deutero-acyl group and alkoxy carbonyl especially, aryloxycarbonyl and aromatic alkoxy carbonyl especially.The example of the acyl group of this character is an alkanoyl, as ethanoyl, and propionyl and butyryl radicals; The virtue alkanoyl is as phenyl acetyl; Aroyl is as benzoyl or toluyl; The aryloxy alkanoyl is as POA; Alkoxy carbonyl, as methoxycarbonyl, ethoxy carbonyl, 2,2,2-trichlorine ethoxy carbonyl, BOC and 2-iodine ethoxy carbonyl; Aromatic alkoxy carbonyl is as CBZ (＂ carbonyl phenoxy group ＂), 4-methoxyl group benzyloxy base carbonyl and FMOC; And aryl sulfonyl, as Mtr.Preferred amido protecting group is BOC and Mtr and CBZ, Fmoc, benzyl and ethanoyl.
Depend on employed blocking group, the amido protecting group is for example used strong acid, easily with TFA or perchloric acid or use other strong inorganic acid, and example hydrochloric acid or sulfuric acid, or strong organic carboxyl acid, as trichoroacetic acid(TCA), or sulfonic acid, remove as Phenylsulfonic acid or p-toluenesulphonic acids.Possible, but dispensable, there is additional inert solvent.Suitable inert solvent is preferably organic, carboxylic acid for example, and as acetate, ether, as tetrahydrofuran (THF) Huo diox, amides, as DMF, or halogenated hydrocarbon, as methylene dichloride, and alcohols, as methyl alcohol, ethanol or Virahol, and water.The mixture of above-mentioned solvent also is suitable.The preferred excessive use of TFA, need not to add any other solvent and while perchloric acid is to use according to the form of mixtures of 9: 1 ratio with acetate and 70% perchloric acid.Easily, the splitted temperature of reaction is at about 0 ℃ and about 50 ℃, between preferred 15 ℃ and 30 ℃ (room temperature).
BOC, OBut and Mtr group can, for example, preferably with TFA in methylene dichloride solution or with the solution in about 3-5N HCl Zai diox, under 15-30 ℃, removed, and the FMOC group can be removed with dimethyl amine, diethylamide or the piperidines solution in DMF of about 5-50% down at 15-30 ℃ simultaneously.
The blocking group (for example CBZ or benzyl) that can remove by hydrogenolysis can, for example, by being removed with hydrogen (for example noble metal catalyst as palladium, is carried on carrier such as the carbon black easily) in the presence of catalyzer.Above-mentioned solvent, for example, alcohols, as methyl alcohol or ethanol, or amides, as DMF, be suitable as solvent here.In general, hydrogenolysis is under the temperature between about 0 ℃ and 100 ℃ and at about 1 crust and 200 crust, preferably at 20-30 ℃ with carry out under 1-10 clings to.The CBZ base can be gone up or go up under 20-30 ℃ by hydrogenolysis at Pd/C (in methyl alcohol/DMF) with ammonium formiate (replacement hydrogen) at for example 5-10% Pd/C (in methyl alcohol) satisfactorily.
The compound of formula I is preferably by allowing the compound of general formula II and the compound reaction of general formula III obtain.Generally, the initial compounds of general formula II and general formula III is novel.Yet they can the known method of use itself prepare.
In the compound of general formula III; L is Cl preferably; Br; I or be modified and the OH base that can participate in reacting, as have the alkyl-alkylsulfonyl oxygen base (optional methyl sulphonyl oxygen base) of 1-6 carbon atom or have the aryl sulfonyl oxygen base (preferably phenyl-or p-methylphenyl-alkylsulfonyl oxygen base) of 6-10 carbon atom.
In general, the compound of general formula II is in inert solvent and at acid binding agent, reacts under the existence of preferred organic bases such as triethylamine, xylidine, pyridine or quinoline.It is desirable to add oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal, or (sic) the faintly acid salt of basic metal or alkaline-earth metal (preferred potassium, sodium, calcium or caesium).
Depend on employed condition, the reaction times is at several minutes with between 14 days, and temperature of reaction is approximately-30 ℃ and 140 ℃, normally between-10 ℃ and 90 ℃, especially between about 0 ℃ and about 70 ℃.
The example of suitable inert solvent is a hydro carbons, as hexane, and sherwood oil, benzene, toluene or dimethylbenzene; Chlorinated hydrocarbons, as trieline, 1,2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Alcohols, as methyl alcohol, ethanol, Virahol, n-propyl alcohol, the propyl carbinol or the trimethyl carbinol; , ethers, as ether, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox; Glycol ethers, as glycol monomethyl methyl ether or ethylene glycol monomethyl ether (methyl glycol or ethyl glycol), or ethylene glycol dimethyl ether (glyme); Ketone is as acetone or butanone; Amides, ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF); Nitrile is as acetonitrile; Sulfoxide is as dimethyl sulfoxide (DMSO) (DMSO); Dithiocarbonic anhydride; Carboxylic acid is as formic acid or acetate; Nitro-compound is as Nitromethane 99Min. or oil of mirbane; The ester class, as ethylhexoate, or water, or the mixture of these solvents.
Also might be with the ester hydrolysis of formula I.This can carry out by means of solvation or hydrogenolysis easily, as above specified, for example is dissolved in NaOH or KOH in diox/water by use, at 0 ℃ and 60 ℃, and the preferred temperature between 10 ℃ and 40 ℃.
Also might be with radicals R
1And/or R
3Change into another kind of R
1And/or R
3
Especially, carboxylic acid can be converted to carboxylicesters.
By reacting with oxyamine and in the presence of catalyzer such as Pd/C, cyano group being changed into amidino groups subsequently with hydrogen reducing N-hydroxyamidines.Also might be with the amino protecting group of hydrogen exchange routine, by removing protecting group with solvation or hydrogenolysis mode, as previously discussed, or for the amino of being protected by common protecting group by discharging with solvation or hydrogenolysis method.
The enough acid of alkali energy of formula I change into associating acid-adducting salt, for example by allowing the alkali of equivalent be concentrated with passing through then to evaporate with acid reaction in inert solvent such as ethanol.The acid that obtains salt harmless on the pharmacology is particularly suitable for this reaction.Therefore, mineral acid, sulfuric acid for example, nitric acid, haloid acid example hydrochloric acid or Hydrogen bromide, phosphoric acid, as ortho-phosphoric acid, or thionamic acid can both use, organic acid also can use, especially aliphatic series, alicyclic, araliphatic, aromatics or heterocycle monobasic or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, valeric acid, diethylacetic acid, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methane or ethane sulfonic acid, ethane disulfonic acid, 2-hydroxyethanesulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene monosulfonic acid and disulfonic acid, or lauryl sulfate.The harmless salt on physiology that forms with acid for example picrate can be owing to separating and/or the compound of purification formula I.
On the other hand, the acid of formula I can be by being converted to metal-salt harmless on its pharmacology or ammonium salt with acid-respons.
Suitable in this article salt especially, sodium, potassium, magnesium, calcium and ammonium salt, with the ammonium salt that replaces, for example dimethyl, diethyl or diisopropyl ammonium salt, one pure amine salt, glycol amine salt or diisopropyl ammonium salt, cyclohexyl or dicyclohexyl ammonium salt or dibenzyl ethylene ammonium salt, and, the salt of arginine or Methionin for example.
The compound of formula I contains one or more chiral centres and therefore exists with racemic form or opticity form.The racemic mixture that is obtained can split into enantiomorph with physics or chemical process by using known method own.Preferably, by forming diastereomer from racemic mixture with the reaction of opticity separating agent.The example of suitable separating agent is that opticity is sour as tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid or lactic acid, or the D of different opticity camphorsulfonic acid such as beta camphor sulfonic acid and L shaped formula.The enantiomer fractionation that the separator column of opticity separating agent (for example dinitrobenzoyl phenylglycocoll) is equipped with in use also is an ideal; Suitable mobile phase is, for example, hexane/isopropyl alcohol/acetonitrile mixture is for example according to volume ratio 82: 15: 3.
Nature also might use aforesaid method, and utilizing is the initial compounds of opticity already, obtains the optically active compounds of formula I.
With some representative compounds of formula I for α
vβ
3And α
vβ
5The test-results that restraining effect obtained is listed in the table below in the I.Provided IC for vitronectin in conjunction with test in the table
50Value, i.e. concentration (nmol/L) when the vitronectin that has suppressed 50% is incorporated into corresponding isolating acceptor.
The table I according to people J.Biol.Chem.265 such as Smith, the IC of the representative compounds of the formula I that the similar method of method of 12267-71 (1990) is obtained
50Value (concentration when the vitronectin that has suppressed 50% is incorporated into corresponding isolating acceptor, nmol/L) and the measured FAB value of this material.
(1)=ethanoyl; (2)=benzyloxycarbonyl; (A)=(S)-camphor-10-base
| R | R 2 | R 3 | ?Y | ?Z | ?FAB | IC 50α vβ 3 | IC 50α vβ 5 |
| (1) | Butyl | H | Propyl group | O | ?471 | ????6.5 | ????55 |
| ?H | Butyl | H | Propyl group | O | ?429 | ????1.1 | ????2.1 |
| (2) | Butyl | H | Propyl group | O | ?563 | ????92 | |
| (2) | (A) | H | Propyl group | O | ?657 | ????61 | ????136 |
| ?H | (A) | H | Propyl group | O | ?523 | ????0.13 | ????0.16 |
| ?H | (A) | Ethyl | Propyl group | O | ?551 | ????16 | ????13 |
| Ethyl | Butyl | H | Propyl group | O | ?457 | ????0.81 | |
| (2) | (A) | H | Butyl | O | ?671 | ????252 | |
| ?H | The 4-tolyl | H | Butyl | O | ?477 | ????4.6 | |
| ?H | Butyl | H | Butyl | O | ?443 | ????6.2 | |
| ?H | (A) | H | Butyl | O | ?537 | ????0.45 |
The drug test data provide the novel cpd of formula I for α
vβ
3And α
vβ
5The evidence of the antagonistic activity of Vitronectic receptor.
With some representative compounds of formula I of the present invention for the results are shown in the following table II that GP II b/ III a restraining effect is obtained.This table has provided IC
50Value, i.e. concentration when the vitronectin that has suppressed 50% is incorporated into corresponding isolating acceptor.
The IC of the representative compounds of table II formula I
50Value (concentration when the vitronectin that has suppressed 50% is incorporated into corresponding isolating acceptor, nmol/L) and measured FAB value.
(1)=ethanoyl; (2)=benzyloxycarbonyl; (A)=(S)-camphor-10-base-----------------
| R 5 | R 2 | R 3 | Y | ?Z | ?FAB | ?IC 50?GPⅡb/Ⅲa |
| (1) | Butyl | H | Propyl group | O | ?471 | ????1860 |
| ?H | Butyl | H | Propyl group | O | ?429 | ????16 |
| (2) | Butyl | H | Propyl group | O | ?563 | ????5600 |
| (2) | (A) | H | Propyl group | O | ?657 | ????167 |
| ?H | (A) | H | Propyl group | O | ?523 | ????1.3 |
| ?H | (A) | Ethyl | Propyl group | O | ?551 | ????78 |
The drug test data provide the evidence of the novel cpd of formula I for the antagonistic activity of GP II b/ III a fibrinogen deceptor.
The invention further relates to salt harmless on the compound of formula I and/or their pharmacology by the purposes on the approach useful in preparing drug formulations non-chemically.In context, if they can enough at least a solids, liquid and/or semi-solid carrier material or auxiliary substance and suitable, with one or more additional activity compound, are made into the proper dosage form.
The invention further relates to the pharmaceutical preparation of salt harmless at least a compound that comprises formula I and/or its pharmacology.
These preparations can be as the medicine in medical treatment or the animal doctor's medicament.The suitable carriers material be suitable for (for example oral) in the intestines, parenteral or topical application or be suitable for suck that spray form is used and not with the organic or inorganic material of novel cpd reaction, water for example, vegetables oil, benzyl alcohol, aklylene glycol, polyoxyethylene glycol, vanay, gelatin, carbohydrate, as lactose or starch, Magnesium Stearate, talcum or Vaseline.For Orally administered, can use tablet, capsule, powder agent, granula, syrup, fruit juice or the drops of tablet, pill, band coating, for rectal administration, suppository can be used,, solution can be used for parenteral administration, the preferred oil or the aqueous solution, with suspension, emulsion or implant, and, can use paste, emulsion or powder agent for topical application.This novel cpd can also be used to make the preparation of injection by freeze-drying and resulting lyophilized products.Described preparation can be sterilized and/or comprise auxiliary substance such as glidant, sanitas, and stablizer and/or wetting agent, emulsifying agent influences salt, buffer substance, dyestuff, flavour agent and/or several additional activity compound, for example one or more VITAMIN of osmotic pressure.
If use as sucking sprays, can use those to comprise the sprays that is dissolved or suspended in the active compound in propelling gas or the propelling gas mixture (for example carbonic acid gas or Chlorofluorocarbons (CFCs)).In context, active compound can use easily with little mill form, might have acceptable solvent, for example ethanol on one or more additional pharmacology.Inhalant solution can use conventional sucker to use.
Harmless salt can be used for control disease as integrin inhibitor, especially vasculogenesis disease, thrombus, myocardial infarction, coronary heart disease, arteriosclerosis, tumour, inflammation and the infection on the pathology on the compound of formula I and their pharmacology.
In order to control the vasculogenesis disease on the pathology, tumour, osteoporosis, inflammation and infection, the preferred compound that uses according to the formula I of claim 1, and/or their harmless salt, wherein R
2It is camphor-10-base.
In context, novel substance can be generally according to using with other commercial similar method of known polypeptide, yet, preferably according to US-A-4472305 in method like the compounds described, preferably with about 0.05 and 500mg, especially 0.5 and such dosage of the every dose unit of 100mg/ use.The dosage of every day is the 0.01-2mg/kg body weight preferably.Yet, different patients' concrete dosage will depend on various factors, for example, depend on the activity of the particular compound of using, depend on the age, body weight, state of health and sex depend on diet, depend on time and the approach used, depend on drainage rate, depend on the combination of medicine and depend on the severity of the disease specific that will treat.Parenteral administration is preferred.
In context, all temperature are with a degree centigrade ℃ expression.In the following embodiments, " conventional aftertreatment " expression: if need, add water, if need, pH is adjusted to the value of 2-10, and this depends on the structure of final product, with ethyl acetate or dichloromethane extraction, two are separated, and organic phase is purified by means of silica gel chromatography and/or by means of crystallization method with dried over mgso and evaporation.
Mass spectrum (MS):
EI (electron bombardment ionization) M
+
FAB (fast atom bombardment) (M+H)
+
Embodiment 1
25g benzyloxycarbonyl-L-tyrosine tertiary butyl ester, 29ml 4-bromo-butyric acid ethyl ester, 18.7g salt of wormwood and the solution of 1.8g hexaoxacyclooctadecane-6-6 in 300ml toluene stirred 12 hours down at 85 ℃.According to the post-treating method of routine, obtain 25.3g (2S)-2-benzyloxy carboxylic acid amides-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] propionic acid tertiary butyl ester (＂ A ＂), be colourless syrup; FAB486.
10% palladium of 1g/gac is added into 10g ＂ A ＂ in the 70ml ethyl acetate, and in the solution in the 20ml methyl alcohol, 10ml water and [sic] 2ml TFA, mixture was with hydrogen hydrogenation at room temperature 4 hours then.After removing catalyzer and after aftertreatment, obtain 8.8g (2S)-2-amino-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester, trifluoroacetate (＂ B ＂); FAB352.
At room temperature 5.5ml triethylamine and 3.9ml 1-butane SULPHURYL CHLORIDE are joined in the solution of 8.8g ＂ B ＂ in the 100ml methylene dichloride, all be stirred 5 hours then.According to conventional post-treating method, obtain 7.9g (2S)-2-butyl-sulfoamido-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB472.
Be in a comparable manner below, by allow ＂ B ＂ with (S)-(+)-reaction of camphor-10-SULPHURYL CHLORIDE, obtain (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB566 and the reaction of 4-tolylsulfonyl-chlorine obtain (2S)-2-tolylsulfonyl-amido-3-[4-(4-oxyethyl group 4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB506.
At room temperature, with 7.9g (2S)-2-butyl-sulfoamido-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] solution stirring of sodium hydroxide solution in the methyl alcohol of 75ml of propionic acid tertiary butyl ester and 10ml 2N 12 hours.According to the post-treating method of routine, obtain (2S)-2-butyl sulfonamide base-3-[4-(3-carboxyl propyl group oxygen the base)-phenyl of colourless pulpous state form] the propionic acid tertiary butyl ester; FAB444.
Be in a comparable manner below, by removing ethyl ester, from (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] propionic acid tertiary butyl ester acquisition (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-carboxyl propyl group oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB538 and from the tertiary butyl (2S)-2-tolylsulfonyl-amido-3-[4-(4-oxyethyl group-4-oxo butyl oxygen base) phenyl] propionic ester obtains (2S)-2-tolylsulfonyl-amido-3-[4-(3-carboxyl propyl group oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB478.
With 1.1g 2-chloro-1-picoline iodide, 3.9ml ethyl diisopropyl amine and 2.8g Z-guanidine add 1.3g (2S)-2 butyl sulfonamide base-3-[4-(the 3-carboxyl propyl group oxygen base) solution of phenyl 1-propionic acid tertiary butyl ester in the DMF of 15ml to, mixture at room temperature stirred 12 hours.According to the post-treating method of routine, obtain 1.0g (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4 oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB619.
Be in a comparable manner below: from (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-carboxyl propyl group oxygen base) phenyl] the propionic acid tertiary butyl ester obtains (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base)-phenyl] the propionic acid tertiary butyl ester, FAB713 and from (2S)-2-tolylsulfonyl-amido-3-[4-(3-carboxyl propyl group oxygen base) phenyl] the propionic acid tertiary butyl ester obtains (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB653.Embodiment 2
Palladium (10% with 250mg, on gac) add 1g (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4 oxo butyl oxygen base) phenyl to] the propionic acid tertiary butyl ester in the solution of 18ml De diox and 2ml water and mixture at room temperature stirred 3 hours.Behind the separating catalyst and according to the post-treating method of routine, obtain 0.78g (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB485.
Be in a comparable manner below: from (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base)-phenyl] propionic acid tertiary butyl ester acquisition (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB579 and from (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester obtains (2S)-2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB519.Embodiment 3
Add 2ml TFA to 0.78g (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo-butyl oxygen base) phenyl] the propionic acid tertiary butyl ester is in the solution of 20ml methylene dichloride, and mixture is stirred 12 hours.According to the post-treating method and the condensation drying of routine, obtain (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl of 0.87g white amorphous powder form] propionic acid, trifluoroacetate; FAB429.
Be in a comparable manner below: from (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid tertiary butyl ester acquisition (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate; FAB523 and from (2S)-2-tolylsulfonyl-amido-3-[4-(4 guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester obtains (2S)-2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4-oxo-butyl oxygen base) phenyl] propionic acid, trifluoroacetate; FAB463.Embodiment 4
Under 0 ℃, add 10 μ l Acetyl Chloride 98Min.s to 50mg (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, stirred 2 hours in the solution of trifluoroacetate in the 5ml pyridine and with mixture.According to the post-treating method of routine, obtain 0.027g (2S)-2-butyl sulfonamide base-3-[4-(4-N-ethanoyl guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid; FAB471.
Be in a comparable manner below: from (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate obtains (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-ethanoyl guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid; FAB565 and from (2S)-2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate obtains (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-ethanoyl guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid; FAB505.Embodiment 5
Add 1ml TFA to 0.05g (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxy-carbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester at room temperature stirred 12 hours in the solution of 5ml methylene dichloride and with mixture.According to the post-treating method of routine, obtain 0.045g (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl]-propionic acid; FAB563.
Be in a comparable manner below: from (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base)-phenyl] propionic acid tertiary butyl ester acquisition (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid; FAB657 and from (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl]-the propionic acid tertiary butyl ester obtains (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-benzyloxy-carbonyl guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid; FAB597.Embodiment 6
Add 5mg p-toluenesulphonic acids to 0.1g (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate and at room temperature stirred mixture 72 hours in 10ml alcoholic acid solution.According to the post-treating method and the condensation drying of routine, obtain 0.055mg (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4 guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid ethyl ester; FAB551.
Be in a comparable manner below: from (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo-butyl oxygen base) phenyl] propionic acid, trifluoroacetate obtains (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4 oxo butyl oxygen base) phenyl] the propionic acid ethyl ester; FAB457 and from (2S)-2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate obtains ethyl (2S)-2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4 oxo butyl oxygen base) phenyl] propionic acid; FAB491.Embodiment 7
In a comparable manner, by allowing benzyloxycarbonyl-L-p-aminophenyl L-Ala tertiary butyl ester and 1-chloro-4-ethoxy butane-1,4-two reactive ketones obtain compound (2S)-2-benzyloxy carboxylic acid amides-3-[4-(3-oxyethyl group-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.By eliminating the Z blocking group, obtain the tertiary butyl (2S)-2 amino-3-[4-(3-oxyethyl group-3-oxopropyl carboxylic acid amides) phenyl] propionic ester (＂ C ＂).
Be by reacting below with relief ＂ C ＂ and 1-butane SULPHURYL CHLORIDE, obtain (2S)-2-butyl sulfonamide base-3-[4-(3-oxyethyl group 3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, react with 4-tolylsulfonyl-chlorine, obtain (2S)-2-tolylsulfonyl-amido-3-[4-(3-oxyethyl group-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, with with the reaction of (S)-(+)-camphor-10-SULPHURYL CHLORIDE, obtain (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-oxyethyl group-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
By remove the material of ethyl ester below obtaining from following formula: (2S)-2-butyl sulfonamide base-3-[4-(2-carboxy ethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-carboxyl-ethyl carboxylic acid amides) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-carboxy ethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 1, by reacting with the Z-guanidine, material below from these materials, obtaining: (2S)-2-butyl sulfonamide base-3-[4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-2-tolylsulfonyl-amido-3-[4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl]-propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 2; remove the Z blocking group; obtain following compound: (2S)-2-butyl sulfonamide base-3-[4-(3-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester; (2S)-and 2-tolylsulfonyl-amido-3-[4-(3-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 3, remove tertiary butyl ester with TFA, obtain following material: (2S)-2-butyl sulfonamide base-3-[4-(3-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate, (2S)-and 2-tolylsulfonyl-amido-3-[4-(3-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate.
Similar to Example 4; by with excess acetyl chloride; from these materials, obtain following compound: (2S)-2-butyl sulfonamide base-3-(4-(3-N-ethanoyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid; (2S)-and 2-tolylsulfonyl-amido-3-[4-(3-N-ethanoyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-N-ethanoyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid.
Similar to Example 5, handle following material (2S)-2-butyl sulfonamide base-3-[4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl with TFA] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(3-N-benzyl-oxygen base carbonyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxamide groups) phenyl] the propionic acid tertiary butyl ester changes into following compound: (2S)-and 2-butyl sulfonamide base-3-[4-(3-N-benzyloxycarbonyl-guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid, (2S)-2-tolylsulfonyl-amido-3-(4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-N-benzyloxycarbonyl guanidine radicals-3-oxopropyl carboxylic acid amides)-phenyl] propionic acid.Embodiment 8
Similar to Example 1, by allowing benzyloxycarbonyl-L-p-aminophenyl L-Ala tertiary butyl ester and 1-chloro-5-ethoxy pentane-1,5-two reactive ketones, and acquisition compound (2S)-2-benzyloxy carboxylic acid amides-3-(4-(4-oxyethyl group-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.Obtain (2S)-2-amino-3-[4-(4-oxyethyl group-4-oxo butyl carboxylic acid amides) phenyl by eliminating the Z blocking group] propionic acid tertiary butyl ester (＂ D ＂).
By reacting with relief ＂ D ＂ and 1-butane SULPHURYL CHLORIDE, obtain (2S)-2-butyl sulfonamide base-3-[4-(4-oxyethyl group-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, react with 4-tolylsulfonyl-chlorine, obtain (2S)-2-tolylsulfonyl-amido-3-[4-(4-oxyethyl group-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, with with the reaction of (S)-(+)-camphor-10-SULPHURYL CHLORIDE, obtain (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-oxyethyl group-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
By from these materials, removing the material of ethyl ester below obtaining: (2S)-2-butyl sulfonamide base-3-[4-(3-carboxyl-propyl group carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(3-carboxyl propyl group carboxylic acid amides) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido-3-[4-(3-carboxyl propyl group carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 1, by reacting with the Z-guanidine, material below from these materials, obtaining: (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyl-oxygen base carbonyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl]-the propionic acid tertiary butyl ester, (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-benzyl-oxygen base carbonyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl]-propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 2; remove the Z blocking group; obtain following compound: (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester; (2S)-and 2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl]-the propionic acid tertiary butyl ester.
Similar to Example 3, remove tertiary butyl ester with TFA, obtain following material: (2S)-2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate, (2S)-and 2-tolylsulfonyl-amido-3-[4-(4-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate.
Similar to Example 4; by with excess acetyl chloride; from these materials, obtain following compound: (2S)-2-butyl sulfonamide base-3-(4-(4-N-ethanoyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid; (2S)-and 2-tolylsulfonyl-amido-3-[4-(4-N-ethanoyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-ethanoyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid.
Similar to Example 5, handle following material (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl with TFA] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(4-N-benzyl-oxygen base carbonyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-2-[(S)-camphor-10-sulfoamido 1-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl-carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester changes into following compound (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxycarbonyl-guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid, (2S)-and 2-tolylsulfonyl-amido-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butyl carboxylic acid amides)-phenyl] propionic acid.Embodiment 9
Similar to Example 1, by allowing benzyloxycarbonyl-L-p-aminophenyl L-Ala tertiary butyl ester and 1-chloro-3-ethyl propyl ether-1,3-two reactive ketones obtain compound (2S)-2-benzyloxy carboxylic acid amides-3-[4-(2-oxyethyl group-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.Obtain (2S)-2-amino-3-[4-(2-oxyethyl group-2-oxo butyl carboxylic acid amides) phenyl by removing the Z blocking group] propionic acid tertiary butyl ester (＂ E ＂).
By reacting with relief ＂ E ＂ and 1-butane SULPHURYL CHLORIDE, obtain (2S)-2-butyl sulfonamide base-3-[4-(2-oxyethyl group-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, react with 4-tolylsulfonyl-chlorine, obtain (2S)-2-tolylsulfonyl-amido-3-[4-(2-oxyethyl group-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, with with the reaction of (S)-(+)-camphor-10-SULPHURYL CHLORIDE, obtain (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-oxyethyl group-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
By from these materials, removing the material of ethyl ester below obtaining: (2S)-2-butyl sulfonamide base-3-[4-(carboxyl-methyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(carboxyl methyl carboxylic acid amides) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(carboxyl methyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 1, by reacting with the Z-guanidine, material below from these materials, obtaining: (2S)-2-butyl sulfonamide base-3-[4-(2-N-benzyl-oxygen base carbonyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl]-the propionic acid tertiary butyl ester, (2S)-2-tolylsulfonyl-amido-3-[4-(2-N-benzyl-oxygen base carbonyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl]-propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-N-benzyloxycarbonyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 2; remove the Z blocking group; obtain following compound: (2S)-2-butyl sulfonamide base-3-[4-(2-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester; (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl]-the propionic acid tertiary butyl ester.
Similar to Example 3, remove tertiary butyl ester with TFA, obtain following material: (2S)-2-butyl sulfonamide base-3-[4-(2-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate, (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid, trifluoroacetate.
Similar to Example 4; by with excess acetyl chloride; from these materials, obtain following compound: (2S)-2-butyl sulfonamide base-3-[4-(2-N-ethanoyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid; (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-N-ethanoyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido 1-3-[4-(2-N-ethanoyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid.
Similar to Example 5, handle following material (2S)-2-butyl sulfonamide base-3-[4-(2-N-benzyloxycarbonyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl with TFA] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-N-benzyl-oxygen base carbonyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester, (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-N-benzyloxycarbonyl guanidine radicals-2-oxoethyl-carboxylic acid amides) phenyl] the propionic acid tertiary butyl ester changes into following compound (2S)-2-butyl sulfonamide base-3-[4-(2-N-benzyloxycarbonyl-guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid, (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-N-benzyloxycarbonyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(2-N-benzyloxycarbonyl guanidine radicals)-2-oxoethyl carboxylic acid amides) phenyl] propionic acid.Embodiment 10
Similar to Example 1, by allowing the reaction of benzyloxycarbonyl-L-tyrosine tertiary butyl ester and 5-bromine valeric acid ethyl ester, obtain compound (2S)-2-benzyloxy carboxylic acid amides-3-[4-(5-oxyethyl group-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester.By removing the Z blocking group, obtain (2S)-2-amino-3-[4-(5-oxyethyl group-5-oxo amyl group oxygen base) phenyl] propionic acid tertiary butyl ester (＂ F ＂).
By reacting with relief ＂ F ＂ and 1-butane SULPHURYL CHLORIDE, obtain (2S)-2-butyl sulfonamide base-3-[4-(5-oxyethyl group-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester, react with 4-tolylsulfonyl-chlorine, obtain (2S)-2-tolylsulfonyl-amido-3-[4-(5-oxyethyl group-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester, with with the reaction of (S)-(+)-camphor-10-SULPHURYL CHLORIDE, obtain (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-oxyethyl group-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester.
By from these materials, removing the material of ethyl ester below obtaining: (2S)-2-butyl sulfonamide base-3-[4-(4-carboxyl-butyl oxygen base) phenyl] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(4-carboxyl-butyl oxygen base) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-carboxybutyl oxygen base) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 1, by reacting with the Z-guanidine, material below from these materials, obtaining: (2S)-2-butyl sulfonamide base-3-[4-(5-N-benzyloxycarbonyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(5-N-benzyloxycarbonyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-N-benzyloxycarbonyl guanidine radicals-5-oxo amyl group oxygen base)-phenyl] the propionic acid tertiary butyl ester.
Similar to Example 2; remove the Z blocking group; obtain following compound: (2S)-2-butyl sulfonamide base-3-[4-(5-guanidine radicals-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester; (2S)-and 2-tolylsulfonyl-amido-3-[4-(5-guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-guanidine radicals-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester.
Similar to Example 3, remove tertiary butyl ester with TFA, obtain following material: (2S)-and 2-butyl sulfonamide base-3-[4-(5-guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid, trifluoroacetate; FAB443 (2S)-2-tolylsulfonyl-amido-3-[4-(5-guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid, trifluoroacetate; FAB477 and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid, trifluoroacetate; FAB537.
Similar to Example 4; by with excess acetyl chloride; from these materials, obtain following compound: (2S)-2-butyl sulfonamide base-3-[4-(5-N-ethanoyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid; (2S)-and 2-tolylsulfonyl-amido-3-[4-(2-N-ethanoyl guanidine radicals-2-oxoethyl carboxylic acid amides) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-N-ethanoyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid.
Similar to Example 5, handle following material with TFA: (2S)-2-butyl sulfonamide base-3-[4-(5-N-benzyl-oxygen base carbonyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester, (2S)-and 2-tolylsulfonyl-amido-3-[4-(5-N-benzyloxycarbonyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid tertiary butyl ester and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-N-benzyloxycarbonyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] the propionic acid tertiary butyl ester changes into following compound (2S)-2-butyl sulfonamide base-3-[4-(5-N-benzyloxycarbonyl-guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid; FAB577 (2S)-2-tolylsulfonyl-amido-3-[4-(5-N-benzyloxycarbonyl-guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid and (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(5-N-benzyloxycarbonyl guanidine radicals-5-oxo amyl group oxygen base) phenyl] propionic acid; FAB671.Embodiment 11
Similar to Example 1, by allowing the reaction of benzyloxycarbonyl-L-tyrosine tertiary butyl ester and 5-bromo-2-oxo valeronitrile, obtain compound (2S)-2-benzyloxy carboxylic acid amides-3-[4-(4-cyano group-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester.
By removing the Z blocking group, obtain compound (2S)-2-amino-3-[4-(4-cyano group-4-oxo butyl oxygen base) phenyl] propionic acid tertiary butyl ester (＂ G ＂).
By allowing the reaction of ＂ G ＂ and 1-butane SULPHURYL CHLORIDE, obtain (2S)-2-butyl sulfonamide base-3-[4-(4-cyano group-4-oxo butyl oxygen base) phenyl] propionic acid tertiary butyl ester (＂ H ＂).
With the heating 12 hours under the solution in the isopropanol 6: 1 is refluxing of the hydroxy amine hydrochloric acid salt of ＂ H ＂ and equimolar amount and sodium bicarbonate.According to the post-treating method of routine, obtain (2S)-2-butyl sulfonamide base-3-[4-(5-amino-5-N-oxyimino-4-oxo amyl group oxygen base) phenyl] propionic acid tertiary butyl ester (＂ J ＂).
At room temperature depress with standard atmosphere, use palladium catalyst (10%, on gac), with the solution hydrogenation of ＂ J ＂ in acetate 2 hours, after catalyst separating, according to the post-treating method of routine, obtain (2S)-2-butyl sulfonamide base-3-[4-(4-amidine-4-oxo butyl oxygen base) phenyl] propionic acid.Embodiment 12
Similar to Example 1, by allow N-benzyloxycarbonyl-N-ethyl guanidine with (2S)-2-butyl sulfonamide base-3-[4-(3-carboxyl propyl group oxygen base) phenyl] propionic acid tertiary butyl ester reaction, obtain (2S)-2-butyl sulfonamide base-3-[4-(4-N-benzyloxycarbonyl-N-ethyl guanidine radicals-4-oxo butyl oxygen base)-phenyl] the propionic acid tertiary butyl ester; FAB647 with (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(3-carboxyl propyl group oxygen base) phenyl] propionic acid tertiary butyl ester reaction, obtain (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-benzyloxycarbonyl-N-ethyl guanidine radicals-4-oxo butyl-oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB741 and with (2S)-2-tolylsulfonyl-amido-3-[4-(3-carboxyl propyl group oxygen base) phenyl] propionic acid tertiary butyl ester reaction, obtain (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-benzyloxycarbonyl-N-ethyl guanidine radicals-4-oxo butyl oxygen base)-phenyl] the propionic acid tertiary butyl ester; FAB681.
Similar to Example 2, remove the Z blocking group, obtain following compound: (2S)-and 2-butyl sulfonamide base-3-[4-(4-N-ethyl guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB513 (2S)-2-[(S)-camphor-10-sulfoamido]-3-[4-(4-N-ethyl guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB607 and (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-ethyl guanidine radicals-4-oxo butyl oxygen base) phenyl] the propionic acid tertiary butyl ester; FAB547.
Similar to Example 3, remove tertiary butyl ester with TFA, obtain following material: (2S)-and 2-butyl sulfonamide base-3-[4-(4-N-ethyl guanidine radicals-4-oxo-butyl oxygen base) phenyl] propionic acid, trifluoroacetate; FAB457 (2S)-2-[(S)-camphor-10-sulfoamido-3-[4-(4-N-ethyl-guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate; FAB551 and (2S)-2-tolylsulfonyl-amido-3-[4-(4-N-ethyl guanidine radicals-4-oxo butyl oxygen base) phenyl] propionic acid, trifluoroacetate; FAB491.
Following examples relate to pharmaceutical preparation:
Embodiment A: injection bottle
The active compound of 100g formula I and the 5g sodium hydrogen phosphate solution in 3 liters of twice distilled water is adjusted to pH6.5 with 2N hydrochloric acid, carries out disinfection and is distributed in the injection bottle by filtration; Solution is then by freeze-drying, and at the sealed under aseptic conditions bottle.Each injection bottle comprises the 5mg active compound.
Embodiment B: suppository
The mixture of 20g formula I active compound and 100g soybean lecithin and 1400g theobroma oil is melted, and is poured into mould neutralization and allows its cooling.Each suppository comprises the 20mg active compound.
Embodiment C: solution
Preparation 1g formula I active compound, 9.38g NaH
2PO
42H
2O, 28.48gNa
2HPO
412H
2O and 0.1g benzene are pricked the solution of chlorine ammonia in twice distilled water of 940ml.It is adjusted to pH6.8, compensates to 1 liter and pass through radiation sterilization.This solution can use with the eye drop form.
Embodiment D: paste
The active compound of the formula I of 500mg mixes under aseptic condition with 99.5g Vaseline.
Embodiment E: tablet
The active compound of the formula I of 1kg, the 4kg lactose, the potato starch of 1.2kg, the mixture of the talcum of 0.2kg and the Magnesium Stearate of 0.1kg is pressed into tablet according to the method for routine, requires each tablet to comprise the active compound of 10mg.
Embodiment F: the tablet of band coating
According to suppressing, apply according to the method for routine coating then with sucrose, potato starch, talcum, imperial glue and dyestuff with the similar method of embodiment E.
Embodiment G: capsule
According to the method for routine, the active compound of impassioned 2kg is divided into hard capsule, requires each capsule to comprise the active compound of 20mg.
Embodiment H: ampulla
The solution of the formula I active compound of 1kg in 60 liters of twice distilled water carries out disinfection by filtration and all assigns in the ampoule then; Solution is then by freeze-drying, at the sealed under aseptic conditions bottle.Each bottle comprise 10mg active compound,
Embodiment I: suck sprays
The formula I active compound of 14g is dissolved in 10 liters of isosmoticity sodium chloride solutions, and this solution is all assigned in the commodity atomizer with pump principle.Solution is ejected in mouth or the nose.Once spray (approximately 0.1ml) dosage corresponding to about 0.14mg.
Claims (11)
1, the compound of formula I
Wherein X does not exist, or has the alkylidene group of 4-8 carbon atom, arylidene, inferior cycloalkanes
Base, or have 1-3 N, O and/or S atom, unsubstituted or by A,
Oxo and/or R
4Replace once, the assorted cycloalkylidene of twice or three times, Y and Z are not exist in all cases independently, or alkylidene group, O, S, NH,
C (=O), and CONH, NHCO, C (=S), SO
2NH, CA=CA ' or
-C ≡ C-, R
1Be H
2N-C (=NH) or H
2N (C=NH)-NH, wherein primary amine groups can also be provided
Conventional amino protecting group or can be by A, Ar or R
5Replace once, twice or three
Inferior, R
2Be A, Ar or inferior aralkyl, R
3Be H or A, R
4Be H, Hal, OA, NHA, NAA ', CN, NO
2, SA,
SOA, SO
2A, SO
2Ar or SO
3H, R
5Be alkanoyl or loop chain alkyloyl with 1-18 carbon atom, one of them,
Two or three methylene radical can be by N, and O and/or S replace,
Ar-CO-or Ar-alkylidene group-CO-, A and A ' are/H or have the alkyl of 1-15 carbon atom in all cases independently
Or cycloalkyl, it is unsubstituted or by R
4Replace once, twice or three times, and its
In one, two, three methylene radical can be by N, O and/or S replace, Ar is monokaryon or the double-core with 0,1,2,3 or 4 N, O and/or S atom
Aromatic ring, it is unsubstituted or by A and/or R
4Replace once, twice or three times, Hal is F, Cl, Br or I, precondition is that at least one primitive that is selected from radicals X, Y and Z must be CH
2And harmless salt on its physiology.
2, according to the enantiomer or the diastereomer of the generalformula of claim 1.
3, according to the compound of the formula I of claim 1, they are: a) (2S)-2-butyl sulfonamide base-3-[4-(4-N-ethanoyl guanidine radicals-4-oxo butoxy) phenyl] propionic acid; B) (2S)-and 2-butyl sulfonamide base-3-[4-(4-guanidine radicals-4 oxo butyl oxygen base) phenyl] propionic acid; C) (2S)-and 2-(camphor-10-sulfoamido)-3-[4-(4-N-ethyl guanidine radicals-4-oxo butoxy) phenyl] propionic acid; D) (2S)-and 2-(camphor-10-sulfoamido)-3-[4-(4-N-benzyloxycarbonyl guanidine radicals-4-oxo butoxy) phenyl] propionic acid; E) (2S)-and 2-(camphor-10-sulfoamido)-3-[4-(4-guanidine radicals-4-oxo butoxy) phenyl] propionic acid; F) ethyl (2S)-2-(camphor-10-sulfoamido)-3-[4-(4-guanidine radicals-4-oxo butoxy) phenyl] propionic ester; G) (2S)-and 2-butyl sulfonamide base-3-[4-(4-N-ethyl guanidine radicals-4-oxo butoxy) phenyl] propionic acid; H) (2S)-and 2-butyl sulfonamide base-3-[4-(5-guanidine radicals-5-oxo pentyloxy) phenyl] propionic acid; I) (2S)-and 2-(camphor-10-sulfoamido)-3-[4-(5 guanidine radicals-5-oxo pentyloxy) phenyl] propionic acid; With harmless salt on their pharmacology.
4, preparation is according to the method for the generalformula and their salt of claim 1, it is characterized in that: a) by discharging the compound of formula I from this derivative with the functional derivative of solvation reagent or hydrogenolysis agent treated generalformula, or b) compound of general formula II
R wherein
1, R
3, R
4, X, Y and Z have meaning same in the claim 1, with the compound reaction of general formula III
R
2-SO
2-L III is R wherein
2Having same meaning of claim 1 and L is Cl, Br, I, OH or esterified after the OH group that can participate in reacting, or c) ester of formula I is hydrolyzed, or d) radicals R
1And/or R
3Be converted to another kind of radicals R
1And/or R
3, and/or e) alkalescence of formula I or acidic cpd be by being converted to its a kind of salt with acid or alkaline purification.
5, a kind of method of useful in preparing drug formulations is characterized in that making the proper dosage form according to harmless salt on the generalformula of claim 1 and/or its pharmacology together with at least a solid, liquid or semi-solid carrier material or auxiliary substance.
6, a kind of pharmaceutical preparation is characterized in that it contains harmless salt on the pharmacology of the compound of at least a formula I of with good grounds claim 1 and/or a kind of this compound.
7, according to salt harmless on the compound of the formula I of claim 1 and their pharmacology as GP II b/ III a antagonist in the purposes aspect control thrombus, myocardial infarction, coronary heart disease and the arteriosclerosis.
8, according to salt harmless on the compound of the formula I of claim 1 and their pharmacology as α
vThe purposes of integrin inhibitor aspect the generation of control pathologic vessels, tumour, osteoporosis, inflammation and infection.
9, according to harmless salt, wherein R on the compound of the formula I of claim 1 and their pharmacology
2Be camphor-10-base, as α
vThe purposes of integrin inhibitor aspect the generation of control pathologic vessels, tumour, osteoporosis, inflammation and infection.
10, according to salt harmless on the compound of the formula I of claim 1 and/or its pharmacology in the purposes aspect the preparation medicine.
11, according to salt harmless on the compound of the formula I of claim 1 and/or its pharmacology in preparation as α
vPurposes on the medicine of integrin inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97195896A CN1223637A (en) | 1996-06-28 | 1997-06-23 | Phenylalamine derivatives as integrin inhibitors |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19625929.0 | 1996-06-28 | ||
| DE19654483.1 | 1996-12-27 | ||
| CN97195896A CN1223637A (en) | 1996-06-28 | 1997-06-23 | Phenylalamine derivatives as integrin inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1223637A true CN1223637A (en) | 1999-07-21 |
Family
ID=5179440
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97195896A Pending CN1223637A (en) | 1996-06-28 | 1997-06-23 | Phenylalamine derivatives as integrin inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1223637A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102961749A (en) * | 2012-11-07 | 2013-03-13 | 温州医学院 | Application of fibrate drugs used as drugs for inhibiting myopia |
| US9636430B2 (en) | 2015-09-16 | 2017-05-02 | The Procter & Gamble Company | Microfluidic delivery system and cartridge having an outer cover |
| US10806816B2 (en) | 2018-05-15 | 2020-10-20 | The Procter & Gamble Company | Microfluidic cartridge and microfluidic delivery device comprising the same |
| US11305301B2 (en) | 2017-04-10 | 2022-04-19 | The Procter & Gamble Company | Microfluidic delivery device for dispensing and redirecting a fluid composition in the air |
| US11691162B2 (en) | 2017-04-10 | 2023-07-04 | The Procter & Gamble Company | Microfluidic delivery cartridge for use with a microfluidic delivery device |
-
1997
- 1997-06-23 CN CN97195896A patent/CN1223637A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102961749A (en) * | 2012-11-07 | 2013-03-13 | 温州医学院 | Application of fibrate drugs used as drugs for inhibiting myopia |
| US9636430B2 (en) | 2015-09-16 | 2017-05-02 | The Procter & Gamble Company | Microfluidic delivery system and cartridge having an outer cover |
| US11305301B2 (en) | 2017-04-10 | 2022-04-19 | The Procter & Gamble Company | Microfluidic delivery device for dispensing and redirecting a fluid composition in the air |
| US11691162B2 (en) | 2017-04-10 | 2023-07-04 | The Procter & Gamble Company | Microfluidic delivery cartridge for use with a microfluidic delivery device |
| US10806816B2 (en) | 2018-05-15 | 2020-10-20 | The Procter & Gamble Company | Microfluidic cartridge and microfluidic delivery device comprising the same |
| US11633514B2 (en) | 2018-05-15 | 2023-04-25 | The Procter & Gamble Company | Microfluidic cartridge and microfluidic delivery device comprising the same |
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