Compounds and formulations for active substance delivery

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds or their pharmaceutically acceptable salts which can be applicable for biologically active substances delivery.

EFFECT: invention refers to pharmaceutical formulations containing the above compounds, and to a method for administering the biologically active substances.

17 cl, 10 tbl, 19 ex

 

[1] This application claims priority under provisional application for U.S. patent No. 60/576,088, filed June 1, 2004, provisional application for U.S. patent No. 60/576,397, filed June 1, 2004, provisional application for U.S. patent No. 60/576,105, filed June 1, 2004, provisional application for U.S. patent No. 60/571,090, filed may 14, 2004, provisional application for U.S. patent No. 60/571,092, filed may 14, 2004, provisional application for U.S. patent No. 60/571,195, filed may 14, 2004, provisional application for U.S. patent No. 60/571,194, filed may 14, 2004, provisional application for U.S. patent No. 60/571,093, filed may 14, 2004, provisional application for U.S. patent No. 60/571,055, filed may 14, 2004, provisional application for U.S. patent No. 60/571,151, filed may 14, 2004, provisional application for U.S. patent No. 60/571,315, filed may 14, 2004, provisional application for U.S. patent No. 60/571,144, filed may 14, 2004, and provisional application for U.S. patent 60/571,089, filed may 14, 2004, each of which is fully included in the description of this application by reference.

The technical field

[2] the Present invention relates to compounds and compositions for delivering active agents, such as biologically or chemically active agents, to a target (body). These compounds are ideal for the formation of non-covalent mixtures with active substances for oral or other is the procedure of introducing into the animal organism. Also described methods of preparation and the introduction of such compositions.

Background of invention

[3] Conventional methods for delivering active substances are often strictly limited to biological, chemical and physical barriers. Typically, these barriers environment imposes, through which the delivery environment directly around the target delivery and/or the target itself. Particularly vulnerable to these barriers biologically and chemically active substances.

[4] Upon delivery into the body of the animal is biologically and chemically active pharmacological and therapeutic agents barriers creates the body. Examples of physical barriers are the skin, the epithelium of lipid bilayers and membranes of various organs, which are relatively impermeable to certain active substances, but which must be overcome to achieve target delivery, for example, the circulatory system. Chemical barriers without limitation include changes in pH in the gastrointestinal (digestive) tract, and the destruction of enzymes.

[5] These barriers are of particular importance in the development of systems for oral delivery. Oral delivery of many active substances would be selected by way of introducing them into the body of animals, if not biological, chemical and physical barriers. To numerous substances that Trad is largely not subject to oral introduction, are biologically or chemically active peptides, such as calcitonin or insulin; polysaccharides, such as mucopolysaccharides, including, without limitation, heparin; heparinoid; antibiotics and other organic substances. In the gastrointestinal tract under the action of acid hydrolysis, enzymes, etc. these substances can quickly inaktivirovanie or destroyed. In addition, acquisitions may impede the size and structure of macromolecular drugs.

[6] the Earliest known methods of oral administration vulnerable pharmacological agents based on joint application of adjuvants (e.g., resorcinol and non-ionic surfactants, such as alerby ether and polyoxyethylene n-hexadecyltrimethyl ether) to artificially increase the permeability of the intestinal walls, as well as at the joint introduction of inhibitors of enzymes (such as trypsin inhibitors, diisopropylfluorophosphate (CSP) and trasilol) to prevent decomposition (agents) enzymes. As delivery systems for insulin and heparin have also been described liposomes. However, the widespread use of such systems drug delivery is impossible, because (1) these systems require toxic amounts of adjuvants or inhibitors; (2) not found suitable loads (transportable agents) with niskama the molecular weight, i.e. active substances; (3) these systems have poor stability and inadequate shelf life during storage; (5) the system is not able to protect the active substance (load); (6) change the active substance, making it harmful; or (7) the system does not allow or stimulate the absorption of the active substance.

[7] For drug delivery use protein microspheres. See, for example, U.S. Patent Nos. 5,401,516; 5,443,841; and Re. 35,862. In addition, for drug delivery using specifically modified amino acids. See, for example, U.S. patent Nos. 5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5,866,536, and the publication of international applications WO 98/49135; WO 00/06534; WO 00/07979; WO 00/40203; WO 00/47188; WO 00/50386; WO 00/59863; WO 01/32130, WO 01/32596, WO 01/44199, WO 01/51454, WO 02/02509, WO 02/15959, WO 02/16309, WO 02/20466, WO 02/19969, WO 02/69937, WO 03/45306.

[8] More recently, to produce polymeric substances, delivering, polymer conjugatively with a modified amino acid or its derivative through a linking group. The modified polymer can be any polymer, but the preferred polymers include, but are not limited to, polyethylene glycol (PEG) and its derivatives. See, for example, the publication of the international application WO 00/40203.

However, there is still a need for a simple cheap delivery systems that are easy to cook and can in different ways delivers them is in the body a wide range of active substances.

Brief description of the invention

[9] the Present invention provides compounds and compositions that facilitate the delivery of active substances. To compounds that facilitate delivery (connection-media), proposed in the present invention include the compounds shown below, and their pharmaceutically acceptable salts:

where:

R1represents -(CH2)m-R8where m=0 or 1;

R2-R6independently selected from the group comprising hydrogen, hydroxyl, halogen, alkyl (C1-C4alkenyl2-C4, quinil2-C4, alkoxy, C1-C4and cyano;

R7selected from the group comprising alkyl, C1-C10alkenyl C2-C10and quinil2-C10;

R8selected from the group comprising cyclopentyl, cyclohexyl and phenyl, in this case, when R8is phenyl, m=1; and

R8possibly substituted by alkyl (C1-C4, alkoxy, C1-C4, halogen or hydroxyl, or a combination.

[10] In one example implementation of R7is1the alkyl.

[11] In another example implementation of R7is2the alkyl.

[12] In another example implementation of R7is3the alkyl.

[13] In another example implementation of R7is C4as the kilometres.

[14] In another example implementation of R7is C5the alkyl.

[15] In another example implementation of R7is6the alkyl.

[16] In another example implementation of R7is7the alkyl.

[17] In another example implementation of R7is8the alkyl.

[18] the Preferred compounds are, inter alia, the following compounds and their salts suitable for pharmaceutical use:

[19] other compounds carriers proposed

the present invention include compounds having the formula: (Compound) and their pharmaceutical acceptable salts, in which:

R1is the I-alkyl (C 1-C6or alkenyl2-C6,

R2-R6chosen independently of one another from the group consisting of hydrogen, hydroxyl, halogen, alkyl (C1-C4alkenyl2-C4, quinil2-C4, alkoxy, C1-C4and cyano, and

R7selected from the group consisting of alkyl, C1-C10alkenyl2-C10and quinil2-C10.

[20] In one example implementation of R2-R6represent independently from each other hydrogen, methyl, halogen, methoxy.

[21] In another example implementation of R2-R6represent independently from each other hydrogen, methyl, chlorine, methoxy.

[22] In another example implementation of R2-R6represent independently from each other hydrogen, methyl, fluorine, methoxy.

[23] In another example implementation of R2-R6represent independently from each other hydrogen, methyl, iodine, methoxy.

[24] In another example implementation of R2-R6represent independently from each other hydrogen, methyl, bromine, methoxy.

[25] In another example implementation of R1is alkyl (C1-C3.

[26] In another example implementation of R1is stands.

[27] In another example implementation of R1is ethyl.

[28] In another example implementation of R1is isopropyl.

[29] is another example implementation of R 2is stands.

[30] In another example implementation of R2is halogen.

[31] In another example implementation of R2is chlorine.

[32] In another example implementation of R2is fluorine.

[33] In another example implementation of R4is stands.

[34] In another example implementation of R4is methoxy.

[35] In another example implementation of R4is halogen.

[36] In another example implementation of R4is chlorine.

[37] In another example implementation of R4is fluorine.

[38] In another example implementation of R4is cyano.

[39] In another example implementation of R7is C1the alkyl.

[40] In another example implementation of R7is C2the alkyl.

[41] In another example implementation of R7is2the alkyl, branched stands.

[42] In another example implementation of R7is3the alkyl.

[43] In another example implementation of R7is3the alkyl, branched stands.

[44] In another example implementation of R7is C4the alkyl.

[45] In another example implementation of R7is C5the alkyl.

[46] In another example implementation of R7is6the alkyl.

[47] In another example implementation of R7is7the alkyl.

[48] In another example implementation of R7 is8the alkyl.

[49] preferred compounds include, inter alia, the following compounds and their pharmaceutically acceptable salts:

The connection 3510-[methyl(4-were) amino]-10-octadecanoate acid

/tr>
The connection 363-[(4-chlorophenyl)(methyl)amino]-3-oxopropionate acid
The connection 373-[(4-chlorophenyl)(ethyl)amino]-3-oxopropionate acid
Compound 385-[(4-chlorophenyl)(ethyl)amino]-4-methyl-5-oxopentanoic acid
Connection 3910-[(4-chlorophenyl) (methyl)amino] -10-octadecanoate acid
The connection 404-[(4-chlorophenyl)(ethyl)amino]-4-oxobutanoic acid
The connection 415-[(4-chlorophenyl)(methyl)amino]-5-oxopentanoic acid

The connection 427-[ethyl(2-were)amino]-7-oxyptera acid
The connection 436-[ethyl(2-were)amino]-6-oxohexanoate acid
The connection 444-methyl-5-[methyl(4-were)amino]-5-oxopentanoic acid
The connection 455-[(4-chlorophenyl)(methyl)amino]-4-methyl-5-oxopentanoic acid
The connection 468-[methyl(2-were)amino]-8-oxooctanoate acid
Connection 475-[ethyl(2-were)amino]-3-methyl-5-oxopentanoic acid

The connection 485-[isopropyl (phenyl amino]-4-methyl-5-oxopentanoic acidThe connection 495-[ethyl(2-were)amino]-4-methyl-5-oxopentanoic acidThe connection 504-[(4-chlorophenyl)(methyl)amino]-3-methyl-4-oxobutanoic acidThe connection 519-[methyl(4-were)amino]-9-oksanalove acidThe connection 528-[ethyl(2-were)amino]-8-oxooctanoate acidThe connection 538-[isopropyl(phenylamino]-8-oxooctanoate acid

The connection 549-[methyl(2-were)amino]-9-oksanalove acid
The connection 556-[ethyl(phenyl)amino]-6-oxohexanoate acid
The connection 567-[ethyl(2-were)amino]-7-oxyptera acid
Connection 579-[ethyl(2-were)amino]-9-oksanalove acid
The connection 5810-[ethyl(phenyl)amino]-10-octadecanoate acid
The connection 615-[ethyl(phenyl)amino]-4-methyl-5-oxopentanoic acid

The connection 624-[ethyl(2-were)amino]-4-oxobutanoic acid
Connection 635-[methyl(4-were)amino]-5-oxopentanoic acid
The connection 64 5-[methyl(2-were)amino]-5-oxopentanoic acid
The connection 655-[isopropyl(phenyl)amino]-5-oxopentanoic acid
Compound 665-[ethyl(phenyl)amino]-4-methyl-5-oxopentanoic acid
Connection 675-[ethyl(phenyl)amino]-5-oxopentanoic acid
The connection 686-[methyl(4-were)amino]-6-oxohexanoate acid

Connection 696-[methyl (2-were)amino]-6-oxohexanoate acid
The connection 706-[ethyl(2-were)amino]-6-oxohexanoate acid
Connection 717-[methyl(4-meth is fenil)amino]-7-oxyptera acid
The connection 727-[methyl(2-were)amino]-7-oxyptera acid
Connection 735-[(4-chlorophenyl)(ethyl)amino]-5-oxopentanoic acid
The connection 746-[(4-chlorophenyl)(methyl)amino]-6-oxohexanoate acid
Connection 757-[(4-chlorophenyl)(methyl)amino]-7-oxyptera acid

The connection 767-[(4-cyanophenyl)(methyl)amino]-7-oxyptera acid
Connection 777-[(4-methoxyphenyl)(methyl)amino]-7-oxyptera acid
The connection 788-[(4-cyanophenyl)(methyl)amino]-8-assocarray acid
Connection 798-[(4-forfinal)(methyl)amino]-8-oxooctanoate acid
The connection 809-[(2-forfinal)(methyl)amino]-9-oksanalove acid
Connection 819-[(4-forfinal)(methyl)amino]-9-oksanalove acid
The connection 827-[(4-chlorophenyl)(ethyl)amino]-7-oxyptera acid

Connection 838-[(4-chlorophenyl)(methyl)amino]-8-oxooctanoate acid
The connection 849-[(4-chlorophenyl)(methyl)amino]-9-oksanalove acid
Connection 859-[isopropyl(phenyl amino]-9-oksanalove acid
Connection 86 9-[ethyl(2-were)amino]-9-oksanalove acid
Connection 8710-[methyl(2-were)amino]-10-octadecanoate acid
The connection 8810-[isopropyl(phenyl)amino]-10-octadecanoate acid
Connection 8910-[ethyl(phenyl)amino]-10-octadecanoate acid

Connection 909-[(4-cyanophenyl)(methyl)amino]-9-oksanalove acid
Connection 919-[(4-methoxyphenyl)(methyl)amino]-9-oksanalove acid
The connection 9210-[(4-cyanophenyl)(methyl)amino]-10-octadecanoate acid
Connection 9310-[(4-methox is phenyl(methyl)amino]-10-octadecanoate acid
Connection 9410-[(2-forfinal)(methyl)amino]-10-octadecanoate acid
Connection 9510-[(4-forfinal)(methyl)amino]-10-octadecanoate acid
Connection 969-[(4-chlorophenyl)(ethyl)amino]-9-oksanalove acid

Connection 9710-[(4-chlorophenyl)(methyl)amino]-10-octadecanoate acid
Connection 9810-[(4-chlorophenyl)(ethyl)amino]-10-octadecanoate acid
Connection 993-methyl-4-[methyl(4-were)amino]-4-oxobutanoic acid
Connection 1003-methyl-4-[methyl(2-were)amino]-4-oxobutanoic acid
Connection 1014-[isopropyl(phenylamino]-3-methyl-4-oxobutanoic acid
Connection 1023-methyl-5-[methyl(4-were)amino]-5-oxopentanoic acid
Connection 1033-methyl-5-[methyl(2-were)amino]-5-oxopentanoic acid

The connection 1044-[ethyl(2-were)amino]-3-methyl-4-oxobutanoic acid
Connection 1054-methyl-5-[methyl(4-were)amino]-5-oxopentanoic acid
The connection 1064-methyl-5-[methyl(2-were)amino]-5-oxopentanoic acid
Connection 1075-[(4-chlorophenyl)(methyl)amino]-3-methyl-5-oxopentanoic acid
The connection 1084-[(4-chlorophenyl)(ethyl)amino]-3-methyl-4-oxobutanoic acid
Connection 1095-[(4-chlorophenyl)(methyl)amino]-4-methyl-5-oxopentanoic acid

The connection 1105-[(4-chlorophenyl) (ethyl)amino]-3-methyl-5-oxopentanoic acid

[50] other compounds of vehicles proposed in the present invention include compounds having the formula:

and their pharmaceutical acceptable salts, with

n = from 1 to 9, and

R1-R5represent, independently from each other, hydrogen, alkyl (C1-C4, alkoxy, C1-C4alkenyl C2-C4, halogen, hydroxyl, -NH-C(O)-CH3or-O-C6H5.

[51] the Preferred compounds of substances-carriers, are, without limitation, compounds having the following formula and their salts:

[52] In one example implementation n=2-8.

[53] In another example implementation n=8.

[54] In another example implementation n=7.

[55] In another example implementation n=6.

[56] al is d example implementation n=5.

[57] In another example implementation n=4.

[58] In another example implementation n=3.

[59] In another example implementation n=2 and the remaining R groups are hydrogens.

[60] In another example implementation n=8 and the remaining R groups are hydrogens.

[61] In another example implementation n=7 and the remaining R groups are hydrogens.

[62] In another example implementation n=6 and the remaining R groups are hydrogens.

[63] In another example implementation n=5 and the remaining R groups are hydrogens.

[64] In another example implementation n=4 and the remaining R groups are hydrogens.

[65] In another example implementation n=3 and the remaining R groups are hydrogens.

[66] In another example implementation n=2 and the remaining R groups are hydrogens.

[67] In another example implementation of R1and R5are hydrogens.

[68] In another example implementation of R1and R5are hydrogens and n=2.

[69] In another example implementation of R3is hydroxyl.

[70] In another example implementation of R3is hydroxyl and N=8.

[71] In another example implementation of R1is hydroxyl.

[72] In another example implementation of R1is hydroxyl and N=8.

[73] In another example implementation of R3is methoxy.

[74] In another example implementation of R3is methoxy and N=2.

[75] In another example implementation of R3what is methoxy and N=3.

[76] In another example implementation of R2and R4are halogen and N=2.

[77] In another example implementation of R2and R4are Fermi.

[78] In another example implementation of R2and R4are Fermi and N=2.

[79] In another example implementation of R1and R3are metelli.

[80] In another example implementation of R1and R3are metelli and N=2.

[81] In another example implementation of R2and R4are metelli, R3is methoxy and N=4.

[82] In another example implementation of R3is isopropyl.

[83] In another example implementation of R3is isopropyl and N=3.

[84] In another example implementation of R1is methoxy.

[85] In another example implementation of R1is methoxy and N=2.

[86] In another example implementation of R3is halogen.

[87] In another example implementation of R3is a halogen and N=2.

[88] In another example implementation of R3is fluorine and N=2.

[89] In another example implementation of R3is methoxy.

[90] In another example implementation of R3is methoxy and N=4.

[91] In another example implementation of R2and R4are metelli.

[92] In another example implementation of R2and R4are metelli and N=2.

[93] In another example implementation of R2and R4are metelli and N=4.

[94] is another example implementation of R 2and R4 are metelli and N=6.

[95] In another example implementation of R2and R3are metelli and N=4.

[96] In another example implementation of R2and R3are metelli and N=2.

[97] In another example implementation of R1and R4are metelli and N=2.

[98] In another example implementation of R1and R4are halogen-free.

[99] In another example implementation of R1and R4are halogen and N=2.

[100] In another example implementation of R1and R4are halogen and N=4.

[101] In another example implementation of R1and R4are harami.

[102] In another example implementation of R1and R4are harami and N=2.

[103] In another example implementation of R1and R4are harami and N=4.

[104] In another example implementation of R1and R4are hydroxyl.

[105] In another example implementation of R1and R4are hydroxyl and N=8.

[106] In one example implementation, the connection 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 128, 129, 130, 132, 133, 134, 136 and/or 138 excluded from connection With.

[107] preferred compounds include, without limitation, the compounds shown below.

[108] Other compounds substances vehicles proposed in the present invention include compounds having the formula:

and their pharmaceutically acceptable salts, with

R1-R4represent, independently from each other hydrogen, alkyl (C1-C4alkenyl2-C4, halogen, alkoxy, C1-C4or hydroxyl.

[109] In one example implementation of R1-R4 represent, independently of one another, hydrogen, methyl, methoxy, halogen, or isopropyl.

[110] In one example implementation of R1-R4 are all hydrogens.

[111] In another example implementation of R2 and R4 are halogen, preferably bromine or preferably chlorine or preferably iodine, or preferably fluorine.

[112] the other is the example of the R2 and R4 are halogen, preferably bromine or preferably chlorine or preferably iodine, and R1 and R3 are hydrogens.

[113] In another preferred example of implementation of the R2 and R4 are isopropylate.

[114] In another preferred example of implementation of the R2 and R4 are isopropylene, and R1 and R3 are hydrogens.

[115] In another preferred example implementation R4 is stands.

[116] In another preferred example implementation R4 is stands and R1-R3 are hydrogens.

[117] In another preferred example implementation R3 is halogen, preferably chlorine.

[118] In another preferred example implementation R3 is halogen, preferably chlorine and R1, R2 and R4 are hydrogens.

[119] In another preferred example implementation R3 is methoxy.

[120] In another preferred example implementation R3 is methoxy and R1, R2 and R4 are hydrogens.

[121] In another preferred example of implementation of R2 is halogen, preferably bromine.

[122] In another preferred example of implementation of R2 is halogen, preferably bromine, and R1, R2 and R4 are hydrogens.

[123] In another preferred example of implementation of R2 is halogen, preferably chlorine.

[124] In another preferred example of implementation of R2 is halogen, preferably chlorine is m, and R1, R3 and R4 are hydrogens.

[125] In another preferred example of implementation of R2 is methoxy.

[126] In another preferred example of implementation of R2 is methoxy, and R1, R3 and R4 are hydrogens.

[127] In another preferred example of implementation of the R2 is the stands.

[128] In another preferred example of implementation of the R2 is the stands, and R1, R3 and R4 are hydrogens.

[129] Preferred compounds-storage media include, without limitation, compounds having the following formula and their salts:

Soedinenie
3-(2-hydroxy-benzoylamine)-butyric acid
Connection 141
3-(3,5-dibromo-2-hydroxy-benzoylamine)-butyric acid
Connection 142
3-(3,5-dichloro-2-hydroxy-benzoylamine)-butyric acid

Connection 143
3-(2-HYDR the XI-3,5-Diod-benzoylamine)-butyric acid
Connection 144
3-(2-hydroxy-3-methyl-benzoylamine)-butyric acid
Connection 145
3-(4-chloro-2-hydroxy-benzoylamine)-butyric acid
Connection 146
3-(2-hydroxy-4-methoxy-benzoylamine)-butyric acid

Connection 147
3-(5-bromo-2-hydroxy-benzoylamine)-butyric acid
Connection 148
3-(5-chloro-2-hydroxy-benzoylamine)-butyric acid
Connection 149
3-(2-hydroxy-5-methoxy-benzoylamine)-butyric acid
Connection 150
3-(2-hydroxy-5-methyl-benzoylamine)-butyric acid

Connection 151
3-(2-hydroxy-3,5-aminobutiramida benzoylamine)butyric acid

[130] Other compounds-media proposed in the present invention include compounds having the formula:

and their pharmaceutically acceptable salts, in which:

one of the groups R1-R5 has the General structure -(CH2)n-COOH,

where n=0-6;

the remaining four members of R1-R5 independently of one another represent hydrogen, C1-C4alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, or hydroxyl; and

R6-R10 independently of one another represent hydrogen, C1-C4alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, or hydroxyl.

[131] In one example implementation, n=0-4.

[132] In another example implementation, n=0.

[133] In another example implementation, n=1.

[134] In another example implementation, R1-R10 are preferably, independently of one another, hydrogen, halogen, stands and methoxy.

[135] In another example implementation, R1-R10 are preferably, independently of one another, chlorine, halogen, stands metoxi.

[136] In another example implementation, when the General structure -(CH2)n-COOH is attached to R1, and the remaining R groups are hydrogens.

[137] In another example implementation, when the General structure -(CH2)n-COOH is attached to R1, and the remaining R groups are hydrogens and n=0.

[138] In another example implementation, when the General structure -(CH2)n-COOH is attached to R1, and the remaining R groups are hydrogens and n=1.

[139] In another example implementation, when the General structure -(CH2)n-COOH is attached to R3, and the remaining R groups are hydrogens.

[140] In another example implementation, when the General structure -(CH2)n-COOH is attached to R3, and the remaining R groups are hydrogens, and n=0.

[141] In another example implementation, when the General structure -(CH2)n-COOH is attached to R3, and the remaining R groups are hydrogens.

[142] In another example implementation, when the General structure -(CH2)n-COOH is attached to R3, and the remaining R groups are hydrogens and n=1.

[143] In another example implementation, R5 is methoxy, when the General structure -(CH2)n-COOH is attached to R2.

[144] In another example implementation, R5 is methoxy, when the General structure -(CH2)n-COOH is attached to R2, and the remaining R groups are hydrogens.

[145] In another example, the real is saved, R5 is methoxy, when the General structure -(CH2)n-COOH is attached to R2, and n=0.

[146] In another example implementation, R5 is methoxy, when the General structure -(CH2)n-COOH is attached to R2, and n=0, and the remaining R groups are hydrogens.

[147] In another example implementation, R1 and R5 are metelli, when the General structure -(CH2)n-COOH is attached to R3.

[148] In another example implementation, R1 and R5 are metelli, when the General structure -(CH2)n-COOH is attached to R3, and the remaining R groups are hydrogens.

[149] In another example implementation, R1 and R5 are metelli, when the General structure -(CH2)n-COOH is attached to R3 and n=0.

[150] In another example implementation, R1 and R5 are metelli, when the General structure -(CH2)n-COOH is attached to R3 and n=0, and the remaining R groups are hydrogens.

[151] In another example implementation, R1 or R5 is methoxy, when the General structure -(CH2)n-COOH is attached to R3 and n=0.

[152] In another example implementation, R1 or R5 is methoxy, when the General structure -(CH2)n-COOH is attached to R3 and n=0, and the remaining R groups are hydrogens.

[153] In another example implementation, R2 or R4 is halogen, preferably chlorine, when the General structure -(CH2)n-COOH is attached to R3.

[154] In another p the iMER implementation, R2 or R4 is halogen, preferably chlorine, when the General structure -(CH2)n-COOH is attached to R3, and the remaining R groups are hydrogens.

[155] In another example implementation, R2 or R4 is halogen, preferably chlorine, when the General structure -(CH2)n-COOH is attached to R3 and n=0.

[156] In another example implementation, R2 or R4 is halogen, preferably chlorine, when the General structure -(CH2)n-COOH is attached to R3 and n=0, and the remaining R groups are hydrogens.

[157] In one example implementation, connection 152, 153, 154, 155, 156, 157, and/or 158 excluded from the connection that is

[158] Other compounds carriers for delivery of substances proposed in the present invention include compounds of formula:

and their pharmaceutically acceptable salts, in which:

n = 1 to 9; and

R1-R9represent, independently of one another, hydrogen, C1-C4alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, or hydroxyl.

[159] According to one preferred example implementation, n=3-7, preferably, in one preferred example implementation, n=3, preferably, in another preferred example implementation, n=4; preferably, in another preferred example implementation, n=5; preferably, in another FAV is Cetelem example implementation, n=6; preferably, in another preferred example implementation, n=7.

[160] According to another preferred example, R1-R8 is hydrogen.

[161] According to another preferred example, R3 is a halogen, preferably, in one example implementation, R3 is chlorine, preferably, in another example implementation, R3 is bromine.

[162] According to another preferred example, R2 is methoxy.

[163] According to another preferred example, R2 is the stands.

[164] According to another preferred example, R3 is methoxy.

[165] According to another preferred example, R3 is stands.

[166] According to another preferred example, R6 is methoxy.

[167] According to another preferred example, R9 is hydrogen.

[168] According to another preferred example, R9 is hydroxyl.

[169] According to another preferred example, R9 is halogen, preferably, in one example implementation chlorine.

[170] According to another preferred example, R3 and R6 are both methoxy.

[171] According to another preferred example, R3 and R6 are both methoxy and the remaining R groups are hydrogen.

[172] According to another preferred example, R2 is the stands and R3 is chlorine.

[173] According to another pre is reverent example, R2 is the stands and R3 is chlorine and the remaining R groups are hydrogens.

[174] According to another preferred example, R2 is the stands and R9 is chlorine.

[175] According to another preferred example, R2 is the stands and R9 is chlorine and the remaining R groups are hydrogens.

[176] According to another preferred example, R3 is stands and R9 is chlorine.

[177] According to another preferred example, R3 is stands and R9 is chlorine and the remaining R groups are hydrogens.

[178] the Preferred connection-carriers for delivery of substances include, without limitation, compounds having the following formula and their salts:

Connection 165
4-(2-(2-hydroxybenzoyl)-5-methoxyphenoxy)butyric acid

[179] Other compounds carriers for delivery proposed in the present invention include compounds having the formula:

and their pharmaceutically acceptable salts, in which:

R1-R5 represent, independently from each other, C1-C4alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, hydroxyl, or-O-(CH2)nWITH THE N (where n=1-12);

at least one of R1-R5 groups has the General structure

-O-(CH2)n-COOH

where n=1-12; and

R6-R10 represent, independently of one another, hydrogen, C1-C4alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, or hydroxyl.

[180] it is Preferable that only one of R1-R5 groups have the formula -(CH2)n-COOH. In other words, four members of R1-R5 represent, independently of one another, hydrogen, C1-C4alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, or hydroxyl and the remaining member of R1-R5 is-O-(CH2)n-COOH (where n=1-12).

[181] In one preferred example of realization of n=1-12.

[182] In another preferred example of realization of n=1-10.

[183] In another preferred example of realization of n=1-6.

[184] In another preferred example of realization of the n=1-4.

[185] In another preferred example of realization of n=10.

[186] In another preferred example of realization of n=4.

[187] In another preferred example of realization of n=1.

[188] When the General structure -(CH2)n-COOH is attached to R1, all other R groups are hydrogens.

[189] When the General structure -(CH2)n-COOH is attached to R1, all other R groups are hydrogens and n=3.

[190] When the General structure -(CH2)n-COOH join is replaced by R3, all other R groups are hydrogens.

[191] When the General structure -(CH2)n-COOH is attached to R3, all other R groups are hydrogens and n=1.

[192] When the General structure -(CH2)n-COOH is attached to R3, all other R groups are hydrogens and n=4.

[193] When the General structure -(CH2)n-COOH is attached to R3, all other R groups are hydrogens and n=10.

[194] Preferred compounds include, but are not limited to, the following compounds and their pharmaceutically acceptable salts:

Connection 175
4-(2-Benzyloxy-phenoxy)-butyric acid

Connection 176
(4-Benzyloxy-phenoxy)acetic acid
Connection 177
11-(2-Benzyloxyphenyl)undecanoate acid
Connection 178
5-(4-Benzyloxy-phenoxy)is Antonova acid

[195] you Can also use a mixture of these compounds carriers.

[196] the Invention also provides a composition containing a compound-media proposed in the present invention, and at least one active substance. These formulations to deliver the active substance in the selected biological system, the biological availability of the active substances is increased or improved as compared with the introduction of active substances without connection carriers.

[197] Also provided a unit dosage form containing these compounds. The unit dose may be in liquid or solid form, for example tablets, capsules or particles, including powder or sachet.

[198] Another variant implementation of the method is the introduction of active substances into the animal organism by introducing a composition containing at least one of the compounds carriers proposed in the present invention, and the active substance. Methods of administration include oral administration, the introduction of the colon and the introduction through the lungs.

[199] Another implementation option is a method of treating diseases or achieve the desired physiological effect in the body of the animal by injecting the composition proposed in the present invention.

[200] Another example implementation is the introduction of the composition proposed in h is standing the invention, in the body of the animal to which the composition will bring a favorable effect, and/or animal that needs the active substance.

[201] Another example implementation is a method for preparing the composition proposed in the present invention, by mixing at least one connection carrier, proposed in the present invention, and at least one active substance.

Detailed description of the invention

Definition

[202] Used here and in the accompanying claims, the singular number include numerous objects, unless the content clearly indicates otherwise. Thus, for example, the term "molecule" means one or more of these molecules, the term "reagent" means one or more of these various reagents, the term "method" includes a equivalent stage or methods known to the typical person skilled in the art that can be modified or replaced by the methods described here.

[203] the Term "polyform" refers to the different crystallographic forms of the substance.

[204] Used herein, the term "hydrate" includes, without limitation, (i) a substance containing water and United with her in molecular form and (ii) a crystalline substance containing one or more water molecules included in the crystal lattice, or kristallicheskoe substance, containing free water

[205] Used herein, the term "MES" includes, without limitation, molecular or ionic complex of molecules or ions of a solvent with molecules or ions of a substance carrier.

[206] the Term "substance-carrier" refers to any compounds-media disclosed or furnished here by reference, including their pharmaceutically acceptable salts.

[207] "Effective amount of the pharmaceutical composition is an amount described pharmaceutical composition, which is effective for the treatment or prevention of a condition subject to which it is entered within a certain period of time, for example, provides a therapeutic effect during the required interval dosing.

[208] the Term "treat", "treating" or "treated" refers to prophylactic to prevent, cure, heal, alleviate, mitigate, modify, cure, improve, or affect the state (e.g., disease), the symptoms of the condition, or a predisposition to the condition.

[209] "an Effective amount of a substance for delivery" represents the number of substance-media, which promotes the absorption of the necessary quantity of the active substance.

[210] the Term "subject" includes mammals, such as rodents, cows, pigs, with the tanks, cats, primates, and particularly humans.

[211] Used herein, the term "CPD" means the area under the curve of the plasma concentration - time", which is calculated by the formula a-line throughout the entire dosing interval, such as 24-hour interval.

[212] the Term "average"facing the pharmacokinetic value (for example, the average peak) represents the average of the pharmacokinetic parameter, if not specified otherwise.

[213] Used herein, the term "approximately" means within 10% of the given value, preferably within 5%, and more preferably within 1% of this value. Alternatively, the term "approximately" means that the value may fall within a scientifically acceptable error range for this type of values that depends on how well you can perform the measurement using the available tools.

[214] "Indication" means a use in which injected a drug or to prevent or treat the condition, and can be used interchangeably with the term "treating", "treated" or "cured".

[215] Used herein, the term "substituted" includes, without limitation, the substitution of any one or any combination of the following substituents: halogen, hydroxide, lkil C 1-C4and alkoxy, C1-C4.

[216] the Terms "alkyl", "alkoxy", "alkylene", "albaniles", "alkyl (Allen)", and "aryl (alkylene)" includes, without limitation, linear and branched alkyl, alkoxy, alkylene, albaniles, alkyl(Allen), and aryl(alkylene)groups, respectively.

[217] the Term "peptide YY" or "PU'u" refers to a polypeptide Peptide YY, been obtained or derived from any species. Thus, the term "PU'u" includes both human full length peptide, containing 36 amino acids, as set forth in SEQ ID NO: International publication No. WO 02/47712 (which is a PCT duplicate Publication of U.S. patent No. 2002/0141985, designed here by reference) and Tatemoto, Proc Natl Acad Sci USA 79:2514-8, 1982, and species variations of PU'u, including, for example, PU'u mice, hamsters, chickens, cows, rats and dogs. The term "agonist PU'u" refers to any compound that causes an effect similar to the action of PU'u, reducing nutrient availability, for example the compound (1)having activity in food intake, gastric emptying, pancreatic secretion, or the sample weight loss, as described in Examples 1, 2, 5, or 6 in WO 02/47712 and in the publication of U.S. patent No. 2002/0141985, and (2) that in the analysis of specific bound receptor Y (Example 10 in WO 02/47712 and Publication of U.S. patent No. 2002/0141985) or when the analysis of the competitive binding of the labeled PU'u or PU'u [3-36] from certain tissues, containing an excess of Y receptors, including, for example, from the field postrema (Example 9 in WO 02/47712 and in the Publication of U.S. patent No. 2002/0141985), and the agonist PU'u is not pancreatic polypeptide. Preferably, the agonists PU'u contacted in these methods of analysis with affinity greater than about 1 μm, and more preferably with affinity greater than from about 1 to about 5 microns.

[218] Such agonists can include a polypeptide having a functional domain of the PU'u, the active fragment of the PU'u, a chemical reagent or a small molecule. Agonists PU'u can be a peptide or ones connections and enable "agonist analogues of PU'u"refers to any compound that is structurally similar to the PU'u and having the activity of PU'u, typically in the strength of binding or otherwise direct or indirect interaction with the receptor PU'u or other receptor or receptors with which the PU'u itself can interact, causing a biological response. Such compounds include derivatives of PU'u, fragments of PU'u, the elongated molecules PU'u containing more than 36 amino acids, truncated molecules PU'u, containing less than 36 amino acids, and substituted molecules PU'u containing one or more different amino acids, or any combination of the above compounds. These compounds also can be modified using the HVL of the ordinary, as philesia (pegylation, amidation, glycosylation, acylation, sulfation, phosphorylation, acetylation and cyclization.

[219] One such analogue agonist PU'u is PU'u [3-36], designated as SEQ ID NO: WO 02/47712 and Publication of U.S. patent No. 2002/0141985; Eberlein, Eysselein et al., Peptides 10:797-803 (1989); and Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994). Polypeptides with numbers in brackets refer to a shortened polypeptides having the sequence of a peptide with a full length in all positions of the amino acids given in parentheses. Thus, PU'u [3-36] has a sequence identical to PU'u for all amino acids from 3 to 36. Immunoreactivity PU'u [3-36] is approximately 40% of the total peptide YY-like immunoreactivity in putting in extracts of human and dog, and from approximately 36% of the total immunoreactivity of peptide YY in the plasma when the starving condition of the subject to slightly above 50% in the fed state. PU'u [3-36] apparently is the product of cleavage of peptide YY, dipeptidyl-peptidase-IV (DPP). Peptide YY[3-36] is, reportedly, a selective ligand at Y2 and Y5 receptors, which appear to be pharmacologically unique in shortened Y analogues of neuropeptides preferably with N atoms at the ends (for example, leaf fragments). Agonist PU'u can contact PU'u receptor with higher or lower, srads the PTO, he demonstrates a longer or a shorter half-life in vivo or in vitro, or is more or less effective than natural DYY.

[220] Other suitable agonists PU'u include agonists described in International publication No. WO 98/20885, which is decorated by reference.

[221] Used herein, the term "heparin" refers to all forms of heparin, including, without limitation, nefrackzionirovannam heparin, heparinoid, dermatan, chondroitin, heparin with low molecular weight (for example, Tinzaparin (including Tinzaparin sodium), heparin, very low molecular weight heparin with ultrasonically weight. Non-limiting examples include, nefrackzionirovannam heparin, for example, heparin sodium (e.g., heparin sodium USP, available from Scientific Protein Labs of Waunakee, Wisconsin). In General, heparin has a molecular weight of from about 1,000 or 5,000 to about 30,000 daltons. The term "heparin and low-molecular weight" refers to incidents in which at least about 80% (by weight) heparin has a molecular weight between about 3,000 and about 9000 daltons. Non-limiting examples of heparin with low molecular weight include, Tinzaparin, enoxaparin and dalteparin. Tinzaparin was approved by the Department of sanitary inspection behind quality of Isaevich food and drug administration (US FDA, USA) for the treatment of acute symptomatic deep vein thrombosis with pulmonary embolism with or without its introduction in conjunction with warfarin sodium. Sodium salt Tinzaparin from Pharmion Corporation™ can be purchased under the trademark Innohep of Boulder, Colorado. The term "heparin, very low molecular weight" refers to incidents in which at least 80% (by weight) heparin has a molecular weight between about 1500 and about 5000 daltons. Non-limiting examples of heparin, very low molecular weight is bemiparin. The term "heparin with a low molecular weight" refers to incidents in which at least about 80% (by weight) heparin has a molecular weight between about 1000 and about 2000 daltons. A non-limiting example of a heparin with a low molecular weight is fondaparinux.

Reagents-media

[222] the Reagent carriers proposed in the present invention may be in the form of a free acid or a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include, without limitation, organic and inorganic salts, for example alkali metal salts, such as sodium, potassium and lithium; salts of alkaline-earth metals such as magnesium, calcium and barium; ammonium salts; basic linakis is the notes, such as lysine and arginine; and organic amines, such as dimethylamine or pyridine. In one example implementation salts are sodium salts. Salts can be mono - or polyvalent salts such as monosodium salt and disodium salt. Salt can also be a solvate, including ethanol solvate and hydrate. Examples of pharmaceutically acceptable salts include, without limitation, sodium salt, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sulphates, phosphates, chlorides, bromides, iodides, acetates, propionate, Hydrobromic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and potassium carbonate. These salts can be prepared by methods known in this field. For example, the sodium salt can be prepared by dissolving the reagent carrier in ethanol and adding aqueous sodium hydroxide. The reagent carrier can be cleaned by recrystallization or fractionation on one or more solid chromatographic media, single or connected in series. Suitable solvents for recrystallization include, without limitation, acetonitrile, methanol and tetrahydrofuran. The fractionation can be performed (i) in a suitable chromatographic media, such as alumina, using mixtures of methane is l/n-propanol as the mobile phase, (ii) using obetovannoi chromatography, using a mixture of triperoxonane acid/acetonitrile as the mobile phase, or (iii) by ion-exchange chromatography using water or a suitable buffer as mobile phase. When using anion-exchange chromatography, it is preferable that the gradient content of sodium chloride was 0-500 mm.

[224] the Reagent carrier may contain a polymer conjugated with a linking group selected from the group consisting of-NHC(O)NH-, -C(O)NH-,-NHC(O), -EA-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, and carbon - carbon, provided that the polymeric reagent carrier is not a polypeptide or polyaminoamide. The polymer may be any polymer, including, without limitation, alternating copolymers, block copolymers and random copolymers, which are safe for mammals. Preferred polymers include, without limitation, polyethylene; polyacrylates; polymethacrylates; poly(oksietilenom); poly(propylene); polypropylenglycol; polyethylene glycol (PEG); and derivatives and combinations. The molecular weight of the polymer in the General case lies in the range from about 100 to about 200,000 daltons. Preferably, stabilometry weight of the polymer was in the range of from about 200 to about 10,000 daltons. In one example implementation, the molecular weight of the polymer lies in the range of from about 200 to about 600 daltons, and more preferably lies in the range of from about 300 to about 550 daltons. U.S. patent No. 6,627,228 feature here is the full link.

[225] the Amount of the reagent carrier in the solid pharmaceutical composition is an effective amount and can be determined for a particular composition by methods known to the person skilled in the art. In General, the weight ratio of the reagent carrier to the active compound is in the range from about 0.1:1 to about 1000:1. The weight ratio will vary depending on the active substance and specific indications, according to which the active substance is injected into the body.

[226] Other suitable reagents-media proposed in the present invention, are described in U.S. Patents Nos. 6,846,844, 6,699,467, 6,693,208, 6,693,208, 6,693,073, 6,663,898, 6,663,887, 6,646,162, 6,642,411, 6,627,228, 6,623,731, 6,610,329, 6,558,706, 6,525,020, 6,461,643, 6,461,545, 6,440,929, 6,428,780, 6,413,550, 6,399,798, 6,395,774, 6,391,303, 6,384,278, 6,375,983, 6,358,504, 6,346,242, 6,344,213, 6,331,318, 6,313,088, 6,245,359, 6,242,495, 6,221,367, 6,180,140, 5,541,155, 5,693,338, 5,976,569, 5,643,957, 5,955,503, 6,100,298, 5,650,386, 5,866,536, 5,965,121, 5,989,539, 6,001,347, 6,071,510, and 5,820,881. Reagents-media proposed in the present invention, as described in the Published US patents Nos. 20050009748, 20040110839, 20040106825, 20040068013, 20040062773, 20040022856, 20030235612,20030232085, 20030225300, 20030198658, 20030133953, 20030078302, 20030072740, 20030045579, 20030012817, 20030008900, 20020155993, 20020127202, 20020120009, 20020119910, 20020102286, 20020065255, 20020052422, 20020040061, 20020028250, 20020013497, 20020001591, 20010039258, and 20010003001. Reagents-media proposed in the present invention, also described in International publication Nos. WO 2005/020925, WO 2004/104018, WO 2004/080401, WO 2004/062587, WO 2003/057650, WO 2003/057170, WO 2003/045331, WO 2003/045306, WO 2003/026582, WO 2002/100338, WO 2002/070438, WO 2002/069937, WO 02/20466, WO 02/19969, WO 02/16309, WO 02/15959, WO 02/02509, WO 01/92206, WO 01/70219, WO 01/51454, WO 01/44199, WO 01/34114, WO 01/32596, WO 01/32130, WO 00/07979, WO 00/59863, WO 00/50386, WO 00/47188, WO 00/40203, and WO 96/30036. Each of the above U.S. patents, published applications U.S. and published international applications, designed here by reference. These reagents carrier can be prepared by methods known in this field, are described, for example, in the aforementioned patents and published patent applications. For example, SNAC can be prepared by methods known in this field, which, for example, described in U.S. patents Nos. 5,650,386 and 5,866,536, and the Publication of patent applications U.S. No. 2002/0065255.

The active substance

[227] the Active substance is suitable for use in the present invention include biologically active substances chemically active substances, including, without limitation, pesticides, pharmaceutical drugs and therapeutic agents. Suitable active substances include substances which become IU is effective, ineffective or destroyed in the gastrointestinal tract, including under the action of acid hydrolysis, enzymes and the like in a suitable active materials include those macromolecular substances, physiochemical characteristics, including size, structure, or charge, prevent or delay the absorption of active substances when administered orally.

[228] for Example, a substance that must get into the body, or which can favorably influence with improved pharmacokinetics, including shipping, for example, when oral bioavailability is limited or insignificant. These substances are biologically or chemically active substances suitable for use in the present invention include, without limitation, macromolecules, such as peptides, including proteins and polypeptides, including dipeptides; hormones; and saccharides, including monosaccharides, polysaccharides, including disaccharides, a mixture of mucopolysaccharides; carbohydrates; lipids; and small polar organic molecules (i.e. polar organic molecules having a molecular weight of 500 daltons or less); nucleosides, other organic compounds; and, in particular, compounds that do not have oral bioavailability or limited oral bioavailability, including those connections, which is do not penetrate (or which penetrates only part of the dose) through the mucous membrane of the gastrointestinal tract and/or susceptible to chemical decomposition by the action of acids and enzymes in the gastro-intestinal the tract; or any combination of them.

[229] Additional examples include, without limitation, the following substances, including synthetic, natural or recombinant sources:

Amylin and Amylin agonists;
Adrenocorticotropin;
Antigens;

Antimicrobial drugs, including antibiotics, antibacterial agents and antifungal drugs; non-limiting examples of antibiotics include preparations of gram-positive actions, bacteriocidal, lipopeptides and cyclic pepcidine antibiotics, such as daptomycin and its analogues;
ANTIMIGRAINE drugs, such as BIBM-4096BS and other protein antagonists, genetically related to calcitonin, sumatriptan succinate;
Antiviral drugs, including acyclovir, valacyclovir;
Atrial natriuretic factor;
Bisphosphonates, including alendronate, clodronate, etidronate, ibandronate, encadrant, minodronate, meridional, olpadronate, pamidronate, risedronate, tiludronate, zoledronate, EV, and YH529;
Calcitonin, including salmon, sea eel, pigs and humans;
Cholecystokinin (CCK) and CCK agonists, including CCK-8;
Kromolin-sodium (chronogical sodium or disodium);
Cyclosporine;
Desferrioxamine (DFO);
Erythropoietin;
Exedy and agonists exedia, including exedy-3, exedy-4;
Filgrastim
Follitropin (recombinant and natural); (follicle stimulating hormone)
The like peptide 1 (GLP-1), glucagon and the like peptide 2 (GLP-2);
Glucocerebrosidase;
Gonadotropin releasing hormone;

The factor stimulating the secretion of growth hormone;
Hormones that stimulate the secretion of growth hormone;
Growth hormones, including human growth hormone (with HGH), recombinant human growth hormone (rcgr), bovine growth hormones, and porcine growth hormones;
Heparin, including nefrackzionirovannam heparin, heparinoid, dermatan, chondroitin, heparin or low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight synthetic heparins, including fondaparinux;
Insulin, including porcine, bovine, human, and human recombinant, optionally containing counterions, including zinc, sodium, calcium and ammonium;
Insulin-like growth factor, including IGF-1;
Interferons, including α (e.g., interferon of alfacon-1(available as Inferge® from Intermune, Inc. Brisbane, California)), β, OMEGA and γ;
Interleukin -1; interleukin -2; interleukin -11; interleukin -21;
Latinizers hormone and hormone releasing latinizers hormone;
Leptin (0 In protein);
Monoclonal antibodies, including Rituxan, TNF-alpha soluble receptors;
Oxytocin;
Parathyroid hormone (PTH), including its fragments, including PTH 1-34 and PTH 1-38;
Peptide YY (PU'u), including PU'u agonists, fragment 3-36;

Prostaglandins;
Protease inhibitors;
Somatostatin;
Thrombopoetin;
Vancomycin;
VA is opression;
Vitamins;
Vaccines, including vaccines against anthrax or plague, influenza and herpes;

[230] in including stimulants secretion, analogs, fragments, mimetics or polyethylene glycol (PEG)-modified derivatives of these compounds; or any combination of them.

Delivery system

[231] the Composition proposed in the present invention contains one or more compounds carriers proposed in the present invention, and one or more active substances. In one example implementation of one or more compounds of media or salts of these compounds, or polyaminoamide or peptides, of which these compounds or salt form one or more blocks can be used as a reagent carrier by mixing with the active substance before putting them to receive part of the introduction.

[232] the Compositions for injection may be in liquid form. The solvent medium may be water, for example, calcitonin salmon, parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol (for example, heparin) and phosphate buffer (for example, for rcgr growth). Other dosing media contain polyethylene glycol. The dosing solutions can be prepared the way of the mixing solution for the connection of the carrier with a solution of the active substance immediately before injection. In another example implementation, the solution of the connection carrier (or active substance) can be mixed with the solid form of the active substance (or compound-media). The connection carrier and the active substance can also be mixed as dry powders. The connection carrier and the active substance can also be added during the process.

[233] the Dosing solutions may optionally contain additives, such as phosphate buffer salt, citric acid, glycols or other dispersing agents. In the solution can be introduced stabilizing additives, preferably with a concentration of between approximately 0.1 and 20% (wt./the volume).

[234] on the other hand, the compositions of the introduction can be in solid form, for example, tablets, capsules or particles, e.g. powder or sachet. Solid dosage forms can be prepared by mixing the solid form of the compound with the solid form of the active substance. In another example implementation, the solid can be obtained from a solution of the compound and the active substance by methods known in this field, such as freeze-drying (lyophilization), precipitation, crystallization and solid-phase dispersion.

[235] the Compositions for administration proposed in the present invention may also contain one or more inhibitors of enzymes. Such inhibitors is Ermentau include, without limitation, such compounds as actionin or ejections and their derivatives. Other enzyme inhibitors include, without limitation, Aprotinin (Trasilol) and inhibitor (Bowman-Tag.

[236] the Amount of active substance used in the composition for administration proposed in the present invention, an effective amount to achieve the purpose for which a particular active substance has been assigned to the patient. In General, the amount of active substance in the composition is pharmacologically, biologically, therapeutically, or chemically effective amount. However, this number may be less than in the case of the composition used in unit dosage form, as such form may contain many compounds connection carrier/active substance or may contain pharmacologically, biologically, therapeutically, or chemically effective amount, divided into several doses. Then the total effective number can be entered in cumulative doses containing, in an amount effective quantity of the active substance.

[237] the Total amount of active substance that is to be used, can be determined by methods known to the person skilled in the art. However, because the compositions proposed in the present invention can transfer the active substance more efficiently, h is m formulations containing one active substance to a subject, you can enter a lower number of biologically or chemically active substances than the number used in the previous unit dosage forms or delivery systems, this achieves the same levels in the blood and/or therapeutic effects.

[238] Described in the present invention the connection carrier to support the delivery of biologically and chemically active substances, in particular, oral, intranasal, sublingual, stomach, putting (intestinal) introduction, including during intraduodenal the introduction, through the introduction of the small intestine and ileum, subcutaneous, oral introduction, through the introduction of the colon, rectum, vaginal, intramuscular and ophthalmic systems introduction introduction through the mucous membrane, as well as overcoming the blood-brain barrier.

[239] the Unit dosage forms can also contain any one or combination of fillers, diluents, disintegrants, lubricants, plasticizers, colorants, flavoring agents, flavorings, sugars, sweeteners, salt and dosing fillers, including, without limitation, water, 1,2-propandiol, ethanol, olive oil or a combination of both.

[240] the Compounds and formulations proposed content of the invention, p is iminime for the introduction of biologically and chemically active substances in the body of any animal, including, without limitation, birds such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and in particular people; and insects.

[241] This system is particularly effective for delivery of chemically or biologically active substances, which otherwise would be destroyed or become less effective due to the conditions in which they fall before you reach your target zone (i.e. the area in which the active ingredient contained in transporting composition, should be released inside the body of the animal into which they entered. In particular, the compounds and formulations proposed in the present invention are useful for oral administration of active substances, especially those that are not normally transported by oral way or for which it is desirable to use an improved delivery method.

[242] the Compositions containing the compounds and active ingredients that are useful for the delivery of active substances in selected biological systems, because they increase or improve the bioavailability of active substances compared to their introduction without reagent carrier. Delivery can be improved by delivering more of the active substance over a period of time, or upon delivery of the active substance for a specific period of time (for example, to implement a faster or slower is th delivery) or upon delivery of the active substance for a certain time or within a certain period of time (for example, long-term delivery).

[243] Another example implementation of the present invention is a method of treating or preventing the disease or achieve the desired physiological effect, as, for example, the methods listed in the table below, in animals with the introduction of the composition proposed in the present invention. Preferably for treating or preventing diseases or achieve the desired physiological effect is to introduce an effective amount of the composition. Specific indications for the application of the active substances can be found in (1) "Physicians' Desk Reference (58th Ed., 2004, Medical Economics Company, Inc., Montvale, NJ), and (2) Fauci, AS, et. al., Harrison''s Principles of Internal Medicine (14th Ed., 1998, McGraw-Hill Health Professions Division, New York), both of which feature here is the link. The active substances are presented in the table below, include their analogs, fragments, mimetics and polyethylenepolypropylene derivatives.

The active substanceDisease and physiological effect
Amylin and milinovi agonistsObesity

Active washes the VA Disease and physiological effect
AdrenocorticotropinHigh cholesterol (to lower cholesterol)
AntigensInfections
Antiviral drugs, including acyclovir, valacyclovirViral infection, including herpes simplex type I and type II
Growth hormones (including recombinant human harmonista and the factors stimulating the secretion of growth hormone and analogues)Growth disturbances
Interferons, including α, β and γViral infection, including chronic cancer, hepatitis, and multiple sclerosis;
Interleukins (e.g. interleukin-1; interleukin-2, interleukin-11 interleukin-21)Viral infection; cancer; cell-mediated immunity; and transplant rejection;
Insulin; insulin-like growth factor IGF-1Diabetes
HeparinThe treatment and prevention of thrombosis, including deep vein thrombosis; prevention of SV is stevania blood
Calcitonin, including salmon, sea eel, pigs and humansOsteoporosis; bone diseases; bone pain; analgesic (including relieving pain associated with osteoporosis or cancer)

The active substanceDisease and physiological effect
Cholecystokinin (CCK) and CCK agonists, including CCK-8Obesity
ErythropoietinAnemia, HIV/HIV therapy for the treatment of anemia; anemia caused by chemotherapeutic action
Atrial natriuretic factorVasodilatation
AntigensInfections
R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (SMRS)Reduction of amyloid deposits and systemic amyloidosis, often (but not always) due to Alzheimer's disease, diabetes type II, and other amyloid-related diseases
Monoclonal antibodies, including Rituxan, TNF-alpha soluble receptors; To prevent transplant rejection; cancer; use in assays for detecting diseases
Leptin (OB protein)Obesity

The active substanceDisease and physiological effect
Somatostatin/octreotideBleeding ulcer; erosive gastritis; bleeding windy rash; diarrhea; acromegaly; pituitary adenomas secreting tireotropina; secretory pancreatic tumor; carcinoid syndrome; reduction ophthalmopathy associated with proptosis/thyroid; reduction patchy edema/retinal degeneration
Protease inhibitorsHIV/AIDS
AdrenocorticotropinHigh cholesterol (to lower cholesterol)
Gonadotropin releasing hormoneDysfunction ovulation (to stimulate ovulation)
OxytocinViolation of the organism at birth (to stimulate muscle contraction)
The Gorm is h, allocating latinizers hormone; follitropinFor regulation of reproductive function
GlucocerebrosidaseDisease of Gaucher (for absorption lipoprotein)
ThrombopoetinThrombocytopenia

The active substanceDisease and physiological effect
Filgrastim (granulocyte colonystimulating factor; GM-CSF, (sargramostim)Reducing the duration of neutropenia caused by chemotherapy, and thereby the treatment and prevention of infections in patients exposed to the action of chemotherapy; growth suppression or destruction of infection Mycobacterium Avium Intracellular (MAC)
ProstaglandinsArterial high blood pressure, hypertension
CyclosporineGraft rejection
VasopressinBedwetting; antidiuretic
Kromolin-sodiumAsthma; allergies
Van is amicin The treatment and prevention of infections caused by bacteria resistant to antimicrobial therapy, including without limitation, resistant to meticillin Staphalococcus aureus and Staph. epidermiditis

The active substanceDisease and physiological effect
Gallium nitrateOsteoporosis disease Paget's disease; suppression of osteoclasts; promoting osteoblastic activity, hypercalcemia, including cancer, associated with hypercalcemia, urethral (urinary tract) malignancy; exhibits antitumor activity; cancers, including urethral cancers and cancers of the bladder; tumors of lymphatic tissue; cancer (including bladder cancer); leukemia; treatment of bone metastases (and associated pain); multiple myeloma, weakening of the immune reaction in tomoike, rejection of allogeneic transformation; the destruction of iron metabolism; activating cell migration; wound healing; mitigation or treatment of infectious processes caused by species of mycobacterium, including, without limitation, mycobacterium tubercolosis, and mycobacterium avium complex
Desferrioxamine (DFO) Iron overload
Parathyroid hormone (PTH), including its fragmentsOsteoporosis; bone disease

The active substanceDisease and physiological effect
Antimicrobial drugsInfection, including, without limitation, infections caused by gram-positive bacteria
VitaminsTreatment and prevention of vitamin deficiency

The active substanceDisease and fiziologicheskii
Bisphosphonates, including alendronate, clodronate, etidronate, ibandronate, encadrant, Mildronat, meridional, olpadronate, pamidronate, risedronate, tiludronate, zoledronate, EV, and YH529Osteoporosis disease Paget's disease; tumors and metastases in the bones (and associated pain); breast cancer; including, as immunostimulating therapy for early stage breast cancer; therapy of bone metastases (and associated pain), including bone metastases associated with breast cancer, cancer prostate lung cancer; the suppression of osteoclast; promoting osteoblastic activity; treatment and/or prevention of loss of mineral density in the bones; multiple myeloma; prevention of complications in the bones associated with malignant osteolysis; fibrous dysplasia; children idiopathic osteopathies; hypercalcemia, urethral (urinary tract) malignancy; syndrome reflex sympathetic dystrophy, acute back pain after a crushed spine fracture, chronic inflammatory articular infiltration, renal bone disease, extratasty calcification, intoxication analgesic, vitamin D, periarticular ossification

The active substanceDisease and fiziologicheskii
ANTIMIGRAINE drugs, such as BIBM-4096BS BIBN4096BS - (1-piperazinecarboxamide N-[2-[5-amino-1-[[4-(4-pyridinyl)-1-piperazinil)carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4(1,4-dihydro-2-oxo-3(N-hintline) -[R-(R*,S*)]-) and other protein antagonists genetically related to calcitonin, sumatriptan succinate;ANTIMIGRAINE drugs; genetically related to the calcitonin peptide antagonist
GlucagonImproved glycemic control(for example, treatment of hypoglycemia and glycemic control reactions), obesity, diagnostic tool for radiological examination of the stomach, duodenum, small intestine and colon; the treatment of acute poisoning, cardiovascular drugs, including, without limitation, calcium channel blockers, beta-blockers
GLP-1, acciden-3, acciden-4Diabetes; improving glycemic control (for example, treatment of hypoglycemia and glycemic control reactions), obesity

The active substanceDisease and physiological effect
Inhibitors dipeptidylpeptidase IV (DPP-4)Diabetes; improving glycemic control (for example, treatment of hypoglycemia), obesity
Vaccines, including vaccines against anthrax or plague, influenza and herpes;Prevention and flow in a more mild form of the disease and infections
Peptide YY (PU'u and PU'u-like peptidesObesity, diabetes, food RA is trojstva, the syndromes of resistance to insulin

[244] for Example, one example implementation of the present invention is a method for the treatment of patients with diabetes or predisposed thereto, by the introduction of insulin in the pharmaceutical composition proposed in the present invention. Other active substances, including those listed in the table above, can also be used in connection with pharmaceutical compositions proposed in the present invention.

[245] At the subsequent introduction of the active substance present in the composition or unit dosage form involved in the circulation. The bioavailability of the substance can be easily estimated by measuring the known pharmacological activity in the blood, for example, increased blood clotting time caused by heparin or a decrease in the circulation of calcium caused by calcitonin. Periodically it is possible to directly measure the levels of circulation of the active substance.

Supplements

[246] the Solid pharmaceutical composition and unit dosage form proposed in the present invention may contain other active substances and farmacevtichesky acceptable additives such as excipients, carriers, diluents, stabilizers, plasticizers, binders, glidant, disintegrant, disintegrating agents, lubricants, & rsquo; s the, film-forming agents, fragrances, flavors, sugar, sweeteners, preservatives, dosing fillers, surfactants, and any combination of any of the foregoing substances. Preferably, these additives are suitable for pharmaceutical use, as, for example, described in the monograph Remington's, The Science and Practice of Pharmacy (Gennaro, A.R., ed., 20thedition, 2003, Mack Pub. Co.), styled here by reference.

[247] Suitable binders include, without limitation, starch, gelatin, sugars (such as sucrose, molasses, and lactose), dihydrate gidrogenfosfat calcium, natural and synthetic gums (such as, Arabian gum, sodium alginate, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and wax.

[248] Suitable glidant include, without limitation, talc, and silicon dioxide (quartz) (for example, fused silica, and colloidal silicon dioxide).

[249] Suitable disintegrant include, without limitation, starches, chromalveolata sodium crosscarmellose sodium, crosspovidone, clay, cellulose (such as purified cellulose, methylcellulose and natrocarbonatite), alginates, prezentatsionnyy corn starch, and gums (such as agar, guar, locust beans, punished, pectin and tragacanthin resin). Pre is respectful disintegrant is chromalveolata sodium.

[250] Suitable fillers include, without limitation, starches such as rice starch), microcrystalline cellulose, lactose (e.g., lactose monohydrate, sucrose, dextrose, mannitol, calcium sulfate, sulfate, calcium sulfate and tricalcium.

[251] Suitable lubricants include, without limitation, stearic acid, stearates such as calcium stearate and magnesium stearate, talc, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, polyethylene glycol, gidrirovannoe cottonseed oil and castor oil.

[252] Suitable surfactants vkluchaut, without limitation, sodium lauryl sulfate, gidroksilirovanii soy lecithin, Polysorbate, and block copolymers of propylene oxide and ethylene oxide.

Dosage forms

[253] the Solid pharmaceutical composition proposed in the present invention, which contains the active substance and the reagent carrier, can be defined as a solid unit dosage form. Dosage form can be, for example, in the form of tablets, sachets or capsules, in particular, hard or soft capsules made of gelatin. Dosage form can provide instant, long-lasting or controlled by the selection of the reagent carrier, heparin and optionally additional active substances.

[254] the Solid pharmaceutical composition and a solid single dosiro the needful form can be prepared as follows. The reagent carrier in solid form is processed (for example, crushed through a sieve 35 mesh (the number of the sieve mesh to the linear inch)) to obtain a powder having a relatively small and preferably of the same size particles. Then the reagent carrier is mixed with the active substance and, optionally, a filler and/or a moisturizing substance using, for example, V-mixer or similar apparatus to obtain a powder mixture.

[255] Separately prepared mixture of moisturizing agents by mixing moisturizing agents, heparin and reagent carrier. The mixture may also contain, for example, water. The moisturizing formula of the mixture is chosen in such a way as to moisten the heparin when it is mixed with the above powder mixture. According to one preferred example, the moisturizing mixture to partially dissolve the reagent carrier when it is mixed with the powder mixture.

[256] the Powder mixture in small quantities to add to the moisturizing mixture with constant stirring. For a homogeneous stirring is continued for a sufficient time (e.g., 15 minutes) after you add all of the powder mixture. The final composition is typically semi-solid, gel or liquid.

[257] Then the composition can be translated in dosage form such as capsule, by methods known is in this area. According to one preferred example, the final composition is Packed into soft or hard gelatin capsules (e.g. hard gelatin capsules of size 0 Licap Capsugel). Other suitable methods are described in U.S. Patents Nos. 6,605,298, 6,458,383, 6,261,601, 5,714,477, and 3,510,561; Published US patents Nos. 2003/0077303 and 2001/0024658; and International publication No. WO 88/10117, all of which feature here.

EXAMPLES

[258] the Following examples illustrate the present invention without limitation. All processes are given by weight, unless otherwise indicated.

[259] the Compounds listed below were studied by the method of proton nuclear magnetic resonance (1H NMR) spectrometer Bruker® at 300 MHz (Bruker-Physik AG, Silberstreifen, GERMANY) or spectrometer JEOL 400 MHz (JEOL USA, Inc., Peabody, MA), using dimethyl sulfoxide (DMSO-d6) as solvent unless otherwise indicated.

[260] analyses Were performed on a liquid chromatograph/mass spectrometer (LC-MS) using Agilent Technologies (Palo Alto, California), LC/MS 1100 (single quadruplet)with the following parameters:

[261] Mobile phase A: 50:950:5 acetonitrile: water: acetic acid (about./about./vol.).

[262] Mobile phase b: 950:50:5 acetonitrile: water: acetic acid (about./about./vol.).

[263] Gradient elution: 4-min linear gradient 0-100% B; total time of one input is 11 minutes.

[264] About the eating of injected sample: 5 µl.

[265] Column: BOND Rapid Resolution Cartridge, SB-C18, 2.1×30 mm, 3.5 ám.

[267] the particle Size catalog # 873700-902.

[268] column Temperature: 40°C.

[269] UV detection at 244 nm.

[270] FFM parameters:

[271] Source: API-ES positive polarity.

[272] scan Settings:

The range of mass numbers: 125.00-600.00

Fragmentor: 60

Gain: 1.0 MMM

Threshold: 150

Spray chamber:

Gas temperature 350 gr.

Drying gas: 12.0 l/min

Pressure; 275.79 kPa

Load capacity 4000

positive/negative.

Example 1 - Preparation of compounds 1-22

[273] Compounds 1-22 were obtained by the method described in U.S. patent No. 6,384,278, which has here the full link.

[274] the Corresponding N-substituted aniline is mixed with the appropriate monoufia dicarboxylic acid and heated in xylene in the presence of boric acid as a catalyst.

Example 2 - preparation of the compounds 23-34 and 59

[275] Dried, 200-ml round bottom flask with 3 necks equipped with a magnetic stirrer with a Teflon coating and a trap Dean-stark with vacuum jacket, on top of which established a reflux condenser with an inlet adapted to supply nitrogen. In the reaction vessel was placed N-isopropyl-N-phenylamine (8,11 g, 60 mmol), boric acid (0,93 g, 15 mmol) and xylene (88 ml). To the reaction mixture when PE is emiliani was added in one portion 7 ethoxy-7-oxalatebuy acid (of 11.29 g, 60 mmol). To return phlegmy the reaction mixture was heated using a heating jacket. The water, which began to stand out with azeotropic distillation, caught in a trap Dean-stark. After 16 hours of irrigation water was collected, and the reaction mixture was left to cool to room temperature. The reaction mixture was diluted with ethyl acetate (100 ml), and washed 2 N. aqueous solution of HCI (50 ml)and then saturated sodium bicarbonate solution (60 ml). A large part of the organic solvent was removed in vacuum. To the residue was added 2 N. aqueous sodium hydroxide solution (60 ml). The mixture was heated at 60°C for 4 hours. After cooling to room temperature the mixture was washed with 60 ml of ethyl acetate. After the aqueous phase was carefully separated from the organic layer, it is evaporated in order to remove any residual ethyl acetate. To the water solution was added ice, and then an aqueous solution of HCl (2 N., 60 ml), which resulted in precipitation of white solid. Before collecting the precipitate through a sintered funnel, for an additional 30 minutes with continued stirring. Collected white solid was effectively washed with water and hexane, before to be placed in vacuum at room temperature for 12 hours to obtain 7,49 g (45%) of 7-[isopropyl(phenyl)amino]-7-exogamous acid as a white solid. HPLC: Inary peak at 4.83 min; MP: 62-63°C.1H NMR (DMSO-d6,) δ: 0.95-0.97 (d, 6H), 1.08-1.10 (m, 2H), of 1.34-1.40 (m, 4H), 1.76-to 1.79 (m, 2H), is 2.09 and 2.13 (m, 2H), 4.81-4.85 (m, 1H), 7.18-7.20 (m, 2H), 7.44-7.46 (m, 3H). Mass (M+1): 278. Anal. the calculation for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.06; H, 8.45; N, 4.99.

[276] Connection 24-34 and 59 were prepared from the appropriate starting materials using the above method.

The compound (24)

[277] HPLC: single peak 4,43 minimum Mass (M+1): 264.1H NMR (400 MHz, DMSO-d6) δ: 0.95(d, 6H), 1.30(m, 2H), 1.40 (m, 2H), 1.80(m, 2H), 2.00(m, 2H), 4.80(m, 1H), 7.15 (m, 2H), 7.40 (m, 3H).13With NMR (100 MHz, DMSO-d6) δ: 21.0, 24.0, 24.5, 33.0, 34.0, 45.0, 128.0, 129.0, 130.0, 138.5, 170.5, 174.0.

The compound (25)

[278] HPLC: single peak at 4,62 minimum Mass (M+1): 264.1H NMR (400 MHz, DMSO-d6) δ: 0.78 (d, 3H), 0.94-0.95(d, 6H), 1.70-1.72(m, 1H), 1.80-1.92 (m, 2H), 2.08-2.15(m, 1H), 2.20-2.30(m, 1H), 4.75-4.90(m, 1H), 7.10-7.20(m, 2H), 7.35-7.50(m, 3H).13C NMR (100 MHz, DMSO-d6) δ: 19.5, 21.0, 27.0, 40.5, 41.0, 45.0, 128.0, 129.0, 130.5, 138.5, 170.0, 174.0.

The compound (26)

[279] HPLC: single peak at 4,19 minimum Mass (M+1): 250.1H NMR (400 MHz, DMSO-d6) δ: 0.65 (d, 3H), 0.84-0.86(1, 3H), 1.80-1.90(m, 3H), 2.01-2.12(m, 2H), 3.49-3.53(q, 2H), 7.09-7.11(d, 2H), 7.20-7.25(m, 1H), 7.30-7.32 (m, 2H).13C NMR (100 MHz, DMSO-d6) δ: 9.18, 15.87, 17.30, 23.35, 39.50, 123.98, 124.72, 125.92, 138.39, 166.17, 168.27, 169.80.

Compound (27)

[280] HPLC: single peak at 3.92 min Mass (M+1): 250.1H NMR (400 MHz, DMSO-d6) δ: 1.13 (m, 2H), 1.37-1.46 (m, 4H), 1.99 (m, 2H), 2.10-2.15 (t, 2H), 3.15 (s, 3H), 7.29-7.37 (m, 3H), 7.42-7.47 (m, 2H).

Connection (2)

[281] HPLC: single peak at 3.72 min Mass (M+1): 236.1H NMR (400 MHz, DMSO-d6) δ: 0.79-0.81 (d, 3H), 1.93-2.02 (m, 3H), 2.16-2.30 (m, 2H), 3.15 (s, 3H), 7.27-7.37 (m, 3H), 7.43-7.48 (m, 2H).

Compound (29)

[282] HPLC: single peak at 3.88 min Mass (M+1): 242.1H NMR (400 MHz, DMSO-d6) δ: 2.21(m, 2H), 2.49 (m, 2H), 3.13 (s, 3H), 7.37 (m, 2H), 7.58 (m, 2H), 12.10 (br., 1H).13C NMR (100 MHz, DMSO-d6) δ: 28.81, 29.0, 36.5, 129.32, 129.58, 132.0, 142.66, 170.58, 173.63.

Connection (30)

[282] HPLC: single peak at 4,82 minimum Mass (M+1): 278.1H NMR (400 MHz, DMSO-d6) δ: 1.02 (m, 4H), 1.32 (m, 4H), 1.86 (m, 2H), 2.05(m, 2H), 2.21 (s, 3H), 3.00 (s, 3H), 7.00 (m, 2H), 7.12 (m, 2H), 11.85 (br., 1H).

The compound (31)

[283] HPLC: single peak of 4.44 min Mass (M+1): 294.1H NMR (400 MHz, DMSO-d6) δ: 1.10 (m, 4H), 1.39 (m, 4H), 1.93 (m, 2H), 2.11 (m, 2H), 3.07 (s, 3H), 3.75 (s, 3H), 6.96 (m, 2H), 7.20 (m, 2H), at 11.93 (br., 1H).

Compound (32)

[284] HPLC: single peak at 4.81 min Mass (M+1): 278.1H NMR (400 MHz, DMSO-d6) δ: 0.97 (t, 3H), 1.10 (m, 4H), 1.39 (m, 4H), 1.90 (m, 2H), 2.13 (m, 2H), 3.58-3.63 (q, 2H), 7.09-7.24 (d, 2H), 7.34 (m, 1H), 7.41-7.45 (m, 2H).

The compound (33)

[285] HPLC: single peak at 5.48 min Mass (M+1): 312.1H NMR (400 MHz, DMSO-d6) δ: 0.96 (t, 3H), 1.10 (m, 4H), 1.40 (m, 4H), 1.91 (m, 2H), 2.12 (m, 2H), 3.60 (q, 2H), 7.27 (d, 2H), 7.46 (m, 2H), at 11.93 (br., 1H).

Compound (34)

[286] HPLC: single peak at to 4.52 min Mass (M+1): 282.1H NMR (400 MHz, DMSO-SB) 5: 1.09(t, 4H), 1.39(t, 4H), 1.93(t, 2H), 2.10-2.14(t, 2H), 3.09(s. MN), 3.75(8 OZ), 7.19(t, 2H), 7.30(t, 2H), 11.91(br., 1H).

Compound (59)

[287] HPLC: single peak 4.71 min Mass (M+1):284. 1H NMR (400 MHz, DMSO-d6) δ: 0.90(t, 3H), 1.35-1.37 (m, 4H), 1.87 (t, 2H), 2.04 (t, 2H), 3.52-3.57 (q, 2H), 7.25 (m, 2H), 7.43 (m, 2H), 11.94 (8, 1H).

Example 3 - preparation of the compounds 111-139

Connection 111 - 4-Oxo-4-fenilalanina acid:

[289] 10 g (56 mmol) of 3-benzoylpropionic acid (commercially available at Sigma-Aldrich Co., St. Louis, MO) was added to 10 ml of water. The mixture was stirred and added 28 ml of 2 n sodium hydroxide (aqueous). The final solution was stirred for 2 hours and after drying by sublimation method, the collected solid product. 1H NMR (d6-DMSO): δ 7.9, d, 2H (aryl H); δ 7.6, t, 1H, (aryl H); δ 7.5, t, 2H (aryl H); δ 3.1, t, 2H (CH2α to carbonyl); δ 2.2, t, 2H (CH2α to COOH); the peak of COOH was not observed due to the presence of water in the sample.

Connection 113 - 10-(4-Hydroxy-phenyl)-10-octadecanoate acid:

[290] In a 500-ml flask equipped with a reflux condenser, under inert atmosphere were placed decandido acid (20 g, 296 mmol) and acetic anhydride (280 ml, 2,96 mol). For irrigation the mixture was heated for 5 hours. Acetic acid and excess acetic anhydride were removed under reduced pressure. The product was used without further purification.

[292] In a 500-ml flask equipped with a mechanical stirrer, under inert atmosphere was added oxocyclohexa-2,11-dione (20 g, to 108.5 mmol), phenol (10,22 g to 108.5 mmol) and 200 ml of carbon disulfide. Added trichloride aluminum (III) (72,34 g, 542 mmol)and the reaction mixture was stirred for 72 hours. Carbon disulphide decantation, and was carefully added to ice up until most of the mixture did not dissolve. The insoluble substance was collected by vacuum filter and washed with 2×100 ml water. Then the solid was dissolved in 100 ml of 1 M aqueous sodium hydroxide and was carefully acidified using 1 M hydrochloric acid (aqueous) to pH=7,5 Resulting dry residue was removed by filtration and the mother liquor continued to acidify to a pH of 2.5. The precipitated crude product was filtered and washed 1×100 ml water. The crude product was dissolved in 100 ml of 1 M aqueous sodium hydroxide solution, was carefully acidified using 1 M aqueous hydrochloric acid solution to pH=7.5 and was filtered precipitated impurities. The original solution was then acidified to pH 2. The crude product was filtered and washed 2×50 ml water. The product is then recrystallized from acetone. The isolated product (1.2 g, 4%) was collected by filtration. Found: From 69.00, H 7.81%; C16H22O4requires: 69.04, N: 7.97% 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 10.3 (bs, 1H (aryl-Oh); δ 7.8 (d, 2H (aryl H); δ 6.8, d, 2H (aryl H); δ 2.9, t, 2H (CH2α to carbonyl); δ 2.2, t, 2H (CH2α to COOH); δ 1.5, multiplet, 4H (CH2group β to the carbonyl and β to COOH), δ 1.3, multiplet, 8H (the rest of CH2-group).

The connection 114 - 10-(2-Hydroxy-phenyl)-10-octadecanoate acid:

[293] In a 100-ml flask placed is whether methylene chloride (50 ml), 9-brandonanoel (7,63 g, 34,2 mmol) and trimethylsilane (4,5 ml, 35.5 mmol) and stirred under nitrogen atmosphere for 20 minutes. Then was added triethylamine (5.0 ml, compared with 35.9 mmol) and the final reaction mixture was stirred for 2 hours at room temperature. Then the reaction mixture was diluted with 80 ml of hexane, filtered, and then concentrated under reduced pressure. The final residue was again diluted with 80 ml of hexane, filtered, and then concentrated under reduced pressure, obtaining 9.7 g (96%) of a yellow liquid, which was used without further purification.

[294] 5,69 g (to 19.3 mmol) of 9-bromo-nonyloxy)-trimethylsilane was added dropwise in an inert atmosphere in a 50 ml flask containing magnesium metal (0,59 g, a 24.3 mmol), 20 ml of tetrahydrofuran and used a small crystal of iodine to initiate the Grignard reaction. In a 100-ml flask under inert atmosphere was cooled solution of salicylic aldehyde (2,1 ml of 19.7 mmol) in 20 ml of tetrahydrofuran, using external ice bath. The cooled solution of the aldehyde was treated with 1.0 M lithium bis(trimethylsilyl)amidon (20,0 ml, 20 mmol). After stirring for 1 hour the reaction mixture of the Grignard reagent was cooled with external ice bath. Then with constant stirring the cooled reaction mixture of the Grignard reagent was added dropwise via cannula to a solution of aldehyde for the 5-minute period. The final reaction mixture was left to warm to room temperature and continued to stir overnight. In the reaction mixture is poured into 40 ml of ethyl acetate and extinguished 15 ml saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed 2×25 ml portions of 4% aqueous solution of hydrochloric acid, and then 1×20 ml portion of brine. The organic layer was dried over sodium sulfate, was filtered, and the solvent was removed under reduced pressure. Residual salicylaldehyde was removed by distillation Kugelbake and the final residue was used without further purification.

[295] In a 100 ml flask was placed 1-(2-hydroxy-phenyl)-undecane-1,11-diol (5.0 g, to 18.9 mmol) and 50 ml of dimethylformamide. There bichromate was added pyridine (32,9 g of 87.5 mmol). (Additive was moderately exothermic.) The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured in 50 ml of ethyl acetate and washed with 200 ml of water, 30 ml of 4% aqueous solution of hydrochloric acid, 30 ml of water, and, finally, 30 ml of brine. Then the organic layer is within 15 minutes was mixed with 10 g of silica gel, dried with sodium sulfate, was filtered, and the solvent was removed under reduced pressure. The crude product is off-white color recrystallized from a mixture of ethanol/water. The product (0.5 g, 10%) was isolated as off-white is th solid substance with a melting point 85-87°C. Organic elemental analysis: found: 69.01, H 8.36%; C16H22O4requires: 69.54, H: 8.02% 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 7.9 dd, 1H (aryl H); δ 7.5, dt, 1H, (aryl H); δ 6.9, complex multiplet, 2H (aryl H), 3.1, t, 2H (CH2α to carbonyl); δ 2.2, t, 2H (CH2α to COOH); δ 1.6, multiplet, 2H (CH2β to the carbonyl), δ 1.5, multiplet, 2H (CH2β to COOH), δ 1.3, multiplet, 8H (the remainder of CH2-group).

Connection 115 - 4-(4-Methoxy-phenyl)-4-oxomalonate acid:

[296] In a 500 ml round bottom flask equipped with a magnetic stirrer, was placed in an inert atmosphere (nitrogen gas) of 5.25 ml (48,3 mmol) of anisole, 4.83 g (48,3 mmol) of succinic anhydride, 125 ml of 1,1,2,2-tetrachlorethane and 125 ml of nitrobenzene. The reaction vessel was cooled by an external water bath and stirred the reaction mixture for 30 minutes. Trichloride aluminum (14.2 g, 106,4 mmol) was added to a pale yellow solution, which was then stained a dark reddish-brown color. The ice bath was removed and the reaction mixture continued to stir at room temperature for 36 hours. Then the reaction mixture was again cooled external water bath. Cooked acidic solution by pouring the solution of 1 N. of hydrogen chloride in 100 ml of chemical glass filled with ice. This solution was carefully added to the reaction mixture, initially dropwise to tejpar, while the reaction mixture with the appearance of a white precipitate was not transparent. After this point, a portion of 10 ml was carefully added to the sample on the reactivity and then add the remaining mixture of ice/acid. Added a second 100 ml of a mixture of ice/acid were removed external ice bath, and clarified the emulsion was stirred for 2 hours. A white precipitate was removed from the emulsion by the method of vacuum filtration. This solid was dissolved in 300 ml of 0.3 M sodium hydroxide solution, washed with 100 ml of ethyl acetate, and acidified to ~pH 11 M hydrochloric acid. Collected by way of the vacuum filtration of the white precipitate was washed 3×100 ml with deionized water and dried. The product (4.7 g, 47%) was isolated as a white solid with a melting point 149-150°C. Organic elementary analysis: found: 63.52, N 5.78%; C11H12O4requires: 63.45; H: 5.81% 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 7.9 (d, 2H (aryl H); δ 7.0, d, 2H (aryl H); δ 3.8, s, 3H (H OMe s); δ 3.2, t, 2H (CH2α to carbonyl); δ 2.5, t, 2H (CH2α to COOH).

The connection 116 - 4-Methoxy-phenyl)-5-oxopentanoic acid:

[297] Compound 116 was obtained similarly to compound 15, except glutamic anhydride instead of succinic anhydride, melting point 141-142°C. Found: 64.65, H 6.34%; C12H14O4requires: 64.85, H: 6.35% 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 7.9 (d, 2H, ar the global N); δ 7.0, d, 2H (aryl H); δ 3.8, s, 3H (H OMe s); δ 3.0, t, 2H (CH2α to carbonyl); δ 2.3, t, 2H (CH2α to COOH)); δ 1.8 quintuplet, 2H (CH2between the other two).

[298] Compound 117 was purchased from Aldrich (St. Louis, MO), catalog number 514683.

[299] Compound 118 was purchased from Aldrich (St. Louis, MO), catalog number W.

[300] Compound 119 was purchased from Aldrich (St. Louis, MO), catalog number S346810.

[301] Compound 120 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7013D.

[302] Compound 121 was purchased from Reike, Aldrich (St. Louis, MO), catalog number S and

Connection 121 - sodium salt of 5-(4-isopropyl-phenyl)-5-oxopentanoic acid:

[303] 5-(4-isopropyl-phenyl)-5-oxo-pentane acid (5 g, of 21.3 mmol) was dissolved in 75 ml of ethanol in a 250 ml flask. Was added sodium hydroxide (0.85 grams, of 21.3 mmol) and the reaction mixture on a rotary evaporator was stirred overnight under reduced pressure. The solid is dried under vacuum and used without further purification. Found: 60.24, H 6.66, Na 9.21%; C14H17O3Na requires: at 61.28; H: 6.98, Na 8.38% 1H NMR (D2O): 5 7.7, d, 2H (aryl H); δ 7.2 (d, 2H (aryl H); δ 2.9, t, 2H (CH2α to carbonyl); δ 2.8, multiplet, 1H, (CH isopropyl group); δ 2.1, t, 2H (CH2α to COOH); δ 1.8, q, 2H (CH2β to both carbonyl and COOH), δ 1.1, d, 6H (CH3's isopropyl group).

[304] Compound 122 was purchased from Aldrich (the UNT-Louis, MO), catalog number W.

[305] Compound 123 was purchased from Reike, Aldrich (St. Louis, MO), catalog number W.

[306] Compound 124 was purchased from Fischer-Scientific (HAMPTON, new Hampshire), Acros, catalog number 17.522.62

[300] Compound 125 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7011D.

[301] Compound 126 was purchased from Reike, Aldrich (St. Louis, MO),catalog number W.

[302] Compound 128 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7012D.

[303] Compound 129 was purchased from Reike, Aldrich (St. Louis, MO), catalog number W.

[304] Compound 130 was purchased from Reike, Aldrich (St. Louis, MO), catalog number V

[305] Compound 132 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7005b.

[306] Compound 133 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7036F.

[307] Compound 134 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7144D

[308] Compound 136 was purchased from Reike, Aldrich (St. Louis, MO), catalog number W.

[309] Compound 138 was purchased from Reike, Aldrich (St. Louis, MO), catalog number 7036D.

Connection 139 - 10-(2,5-dihydroxy-phenyl)-10-octadecanoate acid:

[310] In a 500-ml flask equipped with a reflux condenser, under inert atmosphere were placed decandido acid (20 g, 296 mmol) and acetic anhydride (280 ml, 2,96 mol). The purpose of irrigation, and the mixture was heated in the course is E. 5 hours. Acetic acid and excess acetic anhydride were removed under reduced pressure. The product was used without further purification.

[311] In a 500-ml flask equipped with a mechanical stirrer, under inert atmosphere were placed pre-synthesized oxocyclohexa-2,11-dione (37,95 g, 206 mmol), 1,4-diacetoxybenzoic (20 g, 103 mmol) and 200 ml of carbon disulfide. Added trichloride aluminum (III) (68,7 g, 515 mmol) and the reaction mixture was stirred for 72 hours. Carbon disulphide decantation, and was carefully added to ice up until most of the mixture did not dissolve. The insoluble substance was collected by way of vacuum filtration and washed with 2×100 ml water. Then the solid was dissolved in 50 ml of 1 M aqueous sodium hydroxide solution and was stirred for 1 hour. The solution was acidified using 1 M aqueous solution of hydrochloric acid until pH=2. The precipitated crude product was collected by filtration, re-dissolved in acetonitrile (50 ml) and methylene chloride (15 ml) and left to slowly deposited during the week. The resulting brown product was filtered and recrystallized from a mixture of acetic acid:water 10:3. The product was isolated (0.8 g, 3%) by filtration. Found: 65.55, N 7.69%; C16H22O5requires: 65.29, H: 7.53% 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 11.4, s, 1H (aryl-Oh); δ 9.2, s, 1H (aryl-Oh); δ 7.2 (d, 1H (aryl who); δ 7.0, dd, 1H (aryl H); δ 6.8, d, 1H (aryl H), 3.0, t, 2H (CH2α to carbonyl); δ 2.2, t, 2H (CH2α to COOH); δ 1.6, multiplet, 2H (CH2β to the carbonyl), δ 1.5, multiplet, 2H (CH2β to COOH), δ 1.3, multiplet, 8H (the remainder of CH2-group).

Example 4 - preparation of the compounds 140-151

[312] In General, these compounds were prepared in four stages. First, mixed salicylic acid, substituted appropriately, and ethyl ester of 3-aminobutyric acid with ethylene dichloride (ejh)/hydroxybenzotriazole (peso)/dichloromethane (DHM). Second, added a basic ion-exchange resin a-15/A-21 (available at Rohm and Haas, Philadelphia, Pennsylvania). Third, after partial processing, the product is reacted with trimethylsilanol potassium (TMSC)/tetrahydrofuran (THF). Fourth, was added to the resin IRC-50 (Rhohm & Haas, Philadelphia, Pennsylvania).

[313] In each scintillation tube was placed salicylic acid (of 4.57 mmol), DHM (10 ml), ejh (1,05 g of 5.48 mmol), peso (838 mg, of 5.48 mmol), DMF (2 ml), and ethyl-3-aminobutyrate (600 mg, of 4.57 mmol). All test tubes were tightly closed tubes, was placed on the reaction block J-Kem (J-Kem Scientific Inc., St. Louis, MO)and was dissolved when heated (150 rpm and 35°C) overnight. Controlled by TLC, all reactions have one dominant point. To each vial was added resin Amberlyst-21 and Amberlyst-15 (about 2.5 g, 11 mmol) and p who was odoljeti shaken at ambient temperature overnight. The reaction mixture was filtered, the resin washed DHM (2×5 ml)and the combined filtrates each reaction mixture was collected in a clean scintillation tube. The filtrates were blown in a stream of nitrogen to a volume of approximately 2 ml

[314] In each tube was placed 1.2 M solution trimethylsilanol potassium (TMSC) in THF (10 ml, 12 mmol). In some reaction mixture was added more THF, when it was necessary to obtain a suspension suitable for shaking. All test tubes were tightly closed tubes, was placed on the reaction block J-Kem, and shook when heated (150 rpm, 60°C, 6 h). The reaction block was cooled and to each tube was added the resin IRC-50 (3 g, 30 mmol) for damping potassium salts. If necessary, suspending the resin and facilitate the shaking was added DHM. The reaction mixture was shaken overnight. The reaction mixture was filtered, the resin washed DHM (2×5 ml), if necessary, to dissolve the solids, washed with DMF and the combined filtrates each reaction mixture was collected in a clean scintillation tube. At this stage, the selected small aliquot of the filtrate was diluted with a mixture of 1:1 atsn/N2For LC-YAM. The filtrates were blown in a stream of nitrogen. To remove trace amounts of DMF, the tubes were placed in a vacuum oven at 50°C.

[315] According to LC-MS analysis, some of the reaction mixture still contains the Ali considerable amount of ether. This mixture was re-processed TMSC. To each tube was added 1.2 M solution TMSC in THF (8 ml, 9.6 mmol). All test tubes were tightly closed with a lid, was placed in the reaction block of the Pier, was stirred and heated (60°C, 5 hours). The reaction block was cooled, and to each tube was added the resin IRC-50 (2 g, 20 mmol) to absorb sodium. If necessary, suspending the resin and facilitate the shaking was added DHM. The reaction mixture was stirred all weekend. The reaction mixture was filtered through a layer of quartz, resin and quartz washed DHM (2×5 ml), then with a mixture of 2:5 Meon/DHM (3×7 ml)and the combined filtrates each reaction mixture was collected in a clean scintillation tube. At this stage, the selected small aliquot of the filtrate was diluted with a mixture of 1:1 atsn/H2O for LC-MS. The filtrates were blown in a stream of nitrogen.

[316] All other reaction mixture, remaining from the first treatment TMSC, were placed in a mixture of 10:1 DHM/Meon and was filtered through a layer of quartz, elwira a large number of 10:1 DHM/Meon. At this stage, the selected small aliquot of the filtrate was diluted with a mixture of 1:1 atsn/H2O for LC-YAM. The filtrates were blown in a stream of nitrogen.

Alternative preparation of compounds 140-151:

[317] a 1-l flask with a round bottom placed 3,5-diisopropylsalicylic acid (25,0 g, 112,5 mmol), peso (20.6 g, 135,0 mm is l), ethyl-3-aminobutyrate (18.0 g, 123,7 mmol) and dioxane (400 ml). The resulting mixture was stirred at ambient temperature. Ejh (25,9 g, 135,0 mmol) was added in portions and continued to stir overnight. HPLC analysis of the reaction mixture at this stage showed the presence of the peso, possible trace amounts of a source of salicylic acid and one new product in predominant amounts. Added another portion of ejh (5 g, 26.0 mmol) and left to mix overnight. Another HPLC-analysis showed no significant changes. The reaction mixture was extinguished with water (400 ml) and, using the rotary evaporator, drove dioxane. The resulting mixture of oil/water poured in a 1 l separating funnel and was added DJM (400 ml). Formed a large amount of white solid. Trying to separate the layers, added EtOAc, but to no avail. The mixture was discharged from the separation column, and drove away from her light organic fractions on a rotary evaporator. A mixture of water/oil was extracted with EtOAc (500 ml, then 200 ml). The combined EtOAc layers were washed with an aqueous solution of HCl (10%, 2×200 ml), aqueous NaOH solution (10%, 2×200 ml) and brine solution (50 ml, then 200 ml). The organics were dried over Na2SO4and drove light fractions on a rotary evaporator, getting a brown oil, which contained a small amount of white solid. HPLC analysis showed that white is solid represents the residual amount of the peso, and the desired product is a brown oil. The brown oil was collected by pipette from a flask, trying to keep the pipette has not got a white solid. The brown oil was placed in EtOAc (500 ml), washed with NaOH (10%, 2×200 ml) and dried over Na2SO4. EtOAc drove on a rotary evaporator, getting a brown oil. At this stage the results of the HPLC analysis showed a single predominant peak and the absence of the peso.

[318] the Viscous oil was dissolved in THF (200 ml) and was added TMSC (31.7 g, 247,4 mmol). The resulting viscous mixture was stirred overnight. HPLC analysis indicated the completion of reaction, the presence of one peak. Added resin IRC-50 (37 g, 370 mmol, 1.5 EQ.) and 100 ml DHM for suspension of the resin, and then stirred for several hours. Was filtered, washed resin DHM (3×50 ml) and concentrated on a rotary evaporator to a brown oil. Attempt to recrystallized from a mixture of atsn/acetone was unsuccessful. Based on solubility, at this stage, has determined that the predominant ingredient was salt of potassium. The oil was placed in a mixture of N2O/atsn, was heated until then, until it became clear, was filtered while hot, and cooled to room temperature. The filtrate was treated with aqueous HCl solution, provided the resulting solid precipitate, and crushed into powder to obtain A: 9,13 grams, WAS is: the retention time of 6.7 min 100%, KF 0.47, NMR is consistent with structure, elemental analysis theoretically:66.11, N:8.21, N:4.54 found:65.62, N:8.19, M:4.46.

The number and the name of the connectionMWMS (M+N)Approx. the percentage of purity based on LC-MS
The connection 140
3-(2-hydroxy-benzoylamine)butyric acid
223.230622483
Connection 141381.032638271
3-(3,5-dibromo-2-hydroxy-benzoylamine)butyric acid
Connection 142292.120629277
3-(3,5-dichloro-2-hydroxy-benzoylamine)butyric acid
Connection 143475.023447682
3-(2-hydroxy-3,5-Diod-benzoylamine)butyric acid
Connection 144 237.257723875
3-(2-hydroxy-3-methyl-benzoylamine)butyric acid
Connection 145257.675625882
3-(4-chloro-2-hydroxy-benzoylamine)butyric acid
Connection 146253.257125475
3-(2-hydroxy-4-methoxy-benzoylamine)-butyric acid
Connection 147302.131630382
3-(5-bromo-2-hydroxy-

benzoylamine)butyric acid
Connection 148257.675625878
3-(5-chloro-2-hydroxy-benzoylamine)butyric acid
Soy is inania 149 253.257125477
3-(2-hydroxy-5-methoxy-benzoylamine)butyric acid
Connection 150237.257723882
3-(2-hydroxy-5-methyl-benzoylamine)butyric acid
Connection 151307.393130889
3-(2-hydroxy-3,5-aminobutiramida benzoylamine)butyric acid

Example 5 to Obtain compounds 152-160

[319] Compound 152 was purchased from Transworld Chemical (South Melbourne, Australia).

[320] Compound 153 was purchased from Lancaster (Windham, NH).

[321] Compound 154 was purchased from Avocado (Heysham, Lancashire, England).

[322] Compound 155 was purchased from Aldrich, catalog number 42919 (St. Louis, MO).

[323] Compound 156 was purchased from Sigma-Aldrich (St. Louis, MO).

[324] Compound 157 was purchased from Sigma (St. Louis, MO).

[325] Compound 158 was purchased from Matrix Scientific (Columbia, SC).

ConnectionVE is X
Time
holding
HPLC
Proto
number
The value of KFTemperature
RA
melting
interval
values
CHNCCHNC NCHNR
1525.410
1535.1 min0.1% TFU069.765.46
1546.2 min0.1% TFU074.986.29
1555.210
1565.82 min 0.1% TFU0
1575.420184-18673.675.372.56
1585.470110-11274.365.8274.39
1595.56 minAt 63.475.3962.65
1605.300.367-7073.455.3273.08

Compound 160:

[326] potassium Hydroxide (10,37 g, 184,8 mmol) were crushed in a mortar and pestle to a powder and placed in a 250 ml flask containing 75 ml of dimethyl sulfoxide and methyl ester of 2-hydroxy-Ben is oinoi acid (7,03 g, 46.2 mmol). To this mixture was added benzylbromide (to $ 7.91 g, 46.2 mmol) and to prepare the mixture for 4 hours under stirring. Was added water (100 ml) and stirred the reaction mixture for 30 minutes. Then the reaction mixture was cooled using an external ice bath to 0°C and acidified with concentrated hydrochloric acid to pH 1. The mixture was extracted with 3×230 ml of ethyl acetate. The organic layers were combined and the solvent was removed under reduced pressure. The resulting yellow liquid was dissolved in ethyl acetate (50 ml) and washed 2×30 ml water, then 2×30 ml saline. The organic layer was dried over sodium sulfate, was filtered, and the solvent was removed under reduced pressure. The resulting yellow liquid was dried over vacuum for several days, when it formed a white crystalline solid. The solid product was collected and then dried over vacuum. Product (8,04 g, 76%) was isolated as a white crystalline solid with a melting point 67-70°C. Organic elementary analysis: found: 73.08, H 5.37%; With14H12About3requires 73.45, N 5.32%;

Example 6 - Preparation of compounds 160-167

[326] the Compound F was prepared in accordance with the General scheme, with 2-hydroxybenzophenone alkilirovanie romancelatina in the presence of a base, which was accompanied by what izlojeniem essential part when using trimethylsilane potassium.

[327] the Connection 160 - 6-(2-(2-hydroxybenzoyl) phenoxy) hexanoic acid:

In a 250 ml round bottom flask, equipped with magnetic stirrer and reflux condenser, was placed 10,32 g (48.2 mmol) of 2,2'-dihydroxybenzophenone and 100 ml of dimethyl sulfoxide (DMSO). To the clear solution was added potassium hydroxide (2.91 in g, with 51.9 mmol), pre-crushed to powder. The reaction mixture was heated to 45°C, up until a large part of the solids dissolved. The resulting red suspension was treated 8,80 ml (11,04 g, a 49.5 mmol) of ethyl-6-bromhexinum. After stirring for 20 hours at 25°C, transparent reaction mixture was diluted with aqueous 1% solution of hydrochloric acid and methyl tert-butyl ether (MTBE). The layers were separated. The organic phase is washed with water (2×50 ml) and with brine (1×40 ml), dried over sodium sulfate and concentrated. The resin was placed in 100 ml of tetrahydrofuran (THF) and treated trimethylsilanol potassium (15,09 g, 118 mmol). The orange solution was stirred for 20 hours at 25°C., diluted with 4% aqueous hydrochloric acid solution to pH 7.5, and washed with MTBE. The organic phase was extracted with aqueous 3% sodium bicarbonate solution. The combined aqueous phase was acidified to pH 2 4% aqueous solution of hydrochloric acid and was extracted with 60 ml of MTBE. This organic phase was washed with brine (1×40 ml), is dried over sodium sulfate and concentrated. The residue was purified by way of flash chromatography using 80% hexane/ethyl acetate (introduced with 0.5% acetic acid). Product (4,2 g, 27%) was isolated as off-white solid with a melting point of 89-91°C. Organic elementary analysis: found: 69.50, H 6.04%; C19H20O5requires: 69.50, H: 6.14% 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 11.5 (bs, 1H (OH); δ 7.5, t, 2H (aryl H); δ 7.4, dd, 1H (aryl H); δ 7.3, dd, 1H (aryl H); δ 7.15, d, 1H (aryl H); δ 7.1, t, 1H (aryl H); δ 7.0, d, 1H (aryl H); δ 6.9, t, 1H (aryl H); δ 3.9, t, 2H, (CH2α to O); δ 2.05, t, 2H (CH2α to COOH); δ 1.4, m, 4H (two CH2's); δ 1.0, p, 2H (CH2in the middle of the chain).

[328] the Following compounds were prepared from the corresponding starting compounds using the same method: 161 Connection, the Connection 162, the Connection 163, Connection 164, Connection 165, the Connection 166 and 167 Connection.

[329] Compound 161 - Sodium 8-(2-(2-hydroxybenzoyl) phenoxy) octanoate:

When using 2,2'-dihydroxybenzophenone and ethyl-8-bromooctanoate as starting compounds, were prepared with a named connection and then transferred to the sodium salt as follows: free acid (of 3.56 g of 9.99 mmol) was dissolved in 40 ml of isopropanol and treated with a solution of sodium hydroxide (1.7 ml), prepared from sodium hydroxide (0,90 g of 22.5 mmol) and water (3,7 ml). Added isopropanol and MT is e, which led to the precipitation of solids. When heated this mixture, a large part of the solids dissolved. The remaining solid was removed by filtration. Off-white solid formed upon cooling with dry ice, were isolated by filtration and dried under reduced pressure. Organic elemental analysis: found: 65.02%, H 6.22%; C21H23O5Na requires 66.00, H 6.65%,1H NMR (d6-DMSO): δ 12.6 (bs, 1H (OH); δ 7.41, t, 1H, (aryl H); δ 7.31, t, 1H (aryl H); δ 7.27, dd, 1H (aryl H); δ 7.15, dd, 1H (aryl H); δ 7.03, d, 1H (aryl H); δ 6.97, t, 1H (aryl H); δ 6.91, d, 1H (aryl H); δ 6.65, t, 1H (aryl H); δ 3.83, t, 2H, (CH2α to O); δ 1.82, t, 2H (CH2α to COONa); δ 1.3, m, 4H (two CH2's); δ 1.0, m, 6H (CH2's in the middle of the chain).13With NMR (d6-DMSO): 198.59, 177.35, 161.35, 156.10, 134.56, 131.98, 131.78, 129.55, 128.57, 123.57, 120.18, 118.00, 117.09, 112.51, 67.74, 37.87, 28.83, 28.35, at 28.27, 25.84, 24.87.

[330] Compound 162 - 5-(2-(2-hydroxybenzoyl)-4-methoxyphenoxy) valeric acid (the data of major isomer): LC-MS analysis: m+1 set peak (345). The results of 1H NMR analysis: (d6-DMSO): δ 12.4, ds, 1H (COOH); δ 11.9, bs, 1H (OH); δ 7.47, t, 1H, (aryl H); δ 7.26, dd, 1H (aryl H); δ 7.14, d, 1H (aryl H); δ 7.13, d, 1H (aryl H); δ 7.03, t, 1H (aryl H); δ 6.49, d, 1H (aryl H); δ 6.42, dd, 1H (aryl H); δ 3.95, t, 2H, (CH2α to O); δ 3.79, s, 3H, (CH3O); δ 2.07, t, 2H (CH2β to COOH); δ 1.48, p, 2H (CH2in the chain); δ 1.34, p, 2H (H 2in the chain).13With NMR (d6-DMSO): 199.60, 174.18, 165.97, 163.34, 155.14, 135.14, 131.77, 128.29, 127.83, 120.46, 114.06, 112.69, 107.41, 100.70, 67.51, 55.76, 33.05, 27.80, 20.77.

[331] Compound 163 - 5-(2-(2-hydroxybenzoyl) phenoxy) valeric acid: LC-MS analysis: m+1 set peak (315). The results of 1H NMR analysis: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 11.5 (bs, 1H (OH); δ 7.50, dt, 1H, (aryl H); δ 7.48, dt, 1H, (aryl H); δ 7.35, dd, 1H (aryl H); δ 7.25, dd, 1H (aryl H); δ 7.14, d, 1H (aryl H); δ 7.06, t, 1H (aryl H); δ 6.96, d, 1H (aryl H); δ 6.85, t, 1H (aryl H); δ 3.93, t, 2H, (CH2α to O); δ 2.06, t, 2H (CH2α to COOH); δ 1.42, p, 2H (CH2in the chain); δ 1.29, p, 2H (CH2in the chain).13With NMR (d6-DMSO): 200.59, 174.15, 160.43, 155.71, 135.94, 132.69, 132.22, 128.58, 128.02, 121.50, 120.46, 119.06, 117.30, 112.67, 67.50, 33.05, 27.75, 20.70.

[332] the Connection 164 - 5-(2-(2-hydroxy-5-methoxybenzoyl)-4-methoxyphenoxy) valeric acid: LC-MS analysis: m+1 set peak (375). The results of 1H NMR analysis: (d6-DMSO): δ 12.4, bs, 1H (COOH); δ 12.0, bs, 1H (OH); δ 7.25, d, 1H, (aryl H); δ 7.21, d, 1H, (aryl H); δ 6.66, d, 1H (aryl H); δ 6.62, dd, 1H (aryl H); δ 6.48, d, 1H (aryl H); δ 6.42, dd, 1H (aryl H); δ 3.96, t, 2H, (CH2α 0); δ 3.81, s, 3H, (CH3O); δ 3.80, s, 3H, (CH3O); δ 2.08, t, 2H (CH2α to COOH); δ 1.48, p, 2H (CH2in the chain); δ 1.34, p, 2H (CH2in the chain).13With NMR (d6-DMSO): 198.85, 174.20, 165.62, 164.14, 162.54, 157.11, 135.18, 130.22, 120.60, 114.44, 107.04, 105.51, 100.63, 99.24, 67.55, 55.69, 55.48, 33.06, 27.75, 20.77.

[333] (Compound 166 and 4-(2-(2-hydroxybenzoyl) phenoxy) oil to the slot: LC-MS analysis: m+1 set peak (333). The results of 1H NMR analysis: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.46, m, 2H (aryl H); δ 7.33, dt, 1H (aryl H); δ 7.29, d, 1H (aryl H); δ 6.82, t, 1H (aryl H); δ 3.77, t, 2H, (CH2α to O); δ 1.85, t, 2H (CH2α to COOH); δ 1.35, p, 2H (mid CH2in the circuit). ^C NMR (d6-DMSO): 200.47, 173.92, 160.40, 155.57, 135.97, 132.64, 132.27, 128.64, 128.00, 121.52, 120.56, 119.10, 117.34, 112.62, 66.99, 29.55, 23.92.

[334] Compound 167 - 4-(2-chlorobenzoyl-4-methylphenoxy)butyric acid: LC-MS analysis: m+1 set peak (333). The results of 1H NMR analysis: (d6-DMSO): δ 12.4, bs, 1H (COOH); δ 12.0, bs, 1H (OH); δ 7.23, d, 1H (aryl H, o to O); δ 3.74, t, 2H, (CH2α to O); δ 2.25, s, 3H, CH3); δ 1.84, t, 2H (CH2α to COOH); δ 1.33, p, 2H (mid CH2in the chain).13With NMR (d6-DMSO): 198.76, 173.97, 165.63, 164.10, 162.58, 156.99, 135.11, 130.29, 120.55, 114.45, 107.14, 105.67, 100.67, 99.16, 67.03, 55.69, 55.50, 29.56, at 23.85.

Example preparation of compounds 168-173

[335] (Compound 168) 4-(2-benzoyl-5-methoxyphenoxy)butyric acid:

In a 100-ml mini-block tube equipped with a magnetic stirrer, were placed 4,56 g (20.0 mmol) of 2-hydroxy-4-methoxybenzophenone, 2,70 ml (3,68 g of 18.9 mmol) ethyl 4-bromobutyrate and 40 ml of dimethylformamide (DMF). To the clear solution was added potassium carbonate (2,96 g, with 21.4 mmol). The reaction mixture was heated to 80°C. After stirring for 20 hours at 25°C, transparent reaction mixture was diluted with water. The resulting solid was isolated by filtration. This solid was placed in 3 ml of tetrahydrofuran (THF) and treated 3,10 g (24,0 mmol) of trimethylsilane potassium. The orange solution was stirred for 20 hours at 25°C., diluted with 4% aqueous hydrochloric acid solution to pH 7.5, and washed with MTBE. The organic phase was extracted with 3% aqueous sodium bicarbonate solution. The combined aqueous phase was acidified to pH=2 4% aqueous solution of hydrochloric acid and was extracted with 60 ml of MTBE. This organic phase was washed with brine (1×40 ml), dried over sodium sulfate and concentrated. The resulting solid was purified by grinding into a powder using a mixture of MTBE/hexane. A large part of the product was isolated from the mother liquor. LC-MS analysis: m+1 set peak (315). The results of 1H NMR analysis: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.6, d, 2H, (phenyl H, o to CO); δ 7.56, t, 1H (phenyl N, p (CO); δ 7.44, t, 2H (phenyl N, m); δ 7.35, d, 1H (aryl H, o to CO); δ 6.64, m, 2H (aryl H, m); δ 3.88, t, 2H, (CH2α to O); δ 3.82, s, 3H, (CH3O); δ 1.84, t, 2H (CH2α to COOH); δ 1.53, p, 2H (mid CH2in the chain).13With NMR (d6-DMSO): 195.08, 173.91, 163.17, 158.33, 138.84, 132.37, 131.37, 128.67, 128.24, 120.87, 105.87, 99.02, 66.89, 55.53, 29.45, 23.79.

[336] Other reagents carrier synthesized in the same way: the Connection 169, Connection 170, the Connection 171, Connection 172 and the Connection 173.

[337] (Compound 169) 4-(2-benzoyl-4-chlorophenoxy)butyric acid: LC-MS analysis: m+1 set peak (319). The results of 1H NMR analysis: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 7.64, d, 2H, (fenil is s N, o to CO); δ 7.59, t, 1H (phenyl N, p (CO); δ 7.51, dd, 1H (aryl H, s, CO); δ 7.45, t, 2H (phenyl N, m); δ 7.36, d, 1H (aryl H, o to CO); δ 7.14, d, 1H (aryl H, m); δ 3.87, t, 2H, (CH2α to O); δ 1.84, t, 2H (CH2α to COOH); 51.53, p, 2H (middle of CH2in the chain).13With NMR (d6-DMSO): 194.37, 173.82, 154.74, 136.96, 133.42, 131.56, 130.05, 128.97, 128.62, 128.29, 124.48, 114.61, 67.38, 29.37, 23.79.

[338] (Compound 170) 4-(2-benzoyl-4-bromophenoxy)butyric acid: LC-MS analysis: m+1 set peak (363). The results of 1H NMR analysis: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 7.6, m, 3H (aryl H); δ 7.60, t, 1H (phenyl N, p (CO); δ 7.49, dd, 1H (aryl H, o to CO); δ 7.46, t, 2H (phenyl H, m); δ 7.09, d, 1H (aryl H, m); δ 3.89, t, 2H, (CH2α to O); δ 1.82, t, 2H (CH2α to COOH); δ 1.53, p, 2H (mid CH2in the chain).13With NMR (d6-DMSO): 194.28, 173.81, 155.19, 136.97 134.48, 133.42, 131.06, 130.48, 128.97, 128.62, 115.08, 112.02, 67.33, 29.35, at 23.77.

[339] (Compound 171) 4-(2-(2-chlorobenzoyl-5-methylphenoxy) butyric acid: LC-MS analysis: m+1 set peak (333). The results of 1H NMR analysis: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.54, d, 1H (aryl H); δ 7.4, m, 2H (aryl H); δ 7.33, dt, 1H (aryl H); δ 7.29, d, 1H (aryl H); δ 6.86, m, 2H (aryl H, o to O); δ 3.77, t, 2H, (CH2α to O); δ 2.31, s, 3H, CH3); δ 1.85, t, 2H (CH2α to COOH); δ 1.35, p, 2H (mid CH2in the chain).13With NMR (d6-DMSO): 193.31, 173.81, 158.34, 145.98, 141.38, 130.99, 130.56, 129.48, 129.43, 128.38, 127.00, 123.95, 121.46, 113.43, 66.95, 29.65, 23.70, 21.48.

[340] (Compound 172) 4-(2-(2-chlorobenzoyl-4-methylphe is hydroxy) butyric acid: LC-MS analysis: m+1 set peak (333). The results of 1H NMR analysis: (d6-DMSO): δ 11.95 (bs, 1H (COOH); δ 7.43, m, 3H (aryl H); δ 7.34, m, 3H (aryl H); δ 6.92, d, 1H (aryl H, o to O); δ 3.74, t, 2H, (CH2α to O); δ 2.25, s, 3H, CH3); δ 1.84, t, 2H (CH2α to COOH); δ 1.33, p, 2H (mid CH2in the chain).13With NMR (B6-DMSO): 193.92, 173.81, 156.15, 140.95, 135.37, 131.24, 130.40, 129.65, 129.56, 129.49, 128.62, 127.02, 126.45, 112.95, 67.07,29.65,23.75, 19.80.

[341] (Compound 173) 4-(2-benzoyl-4-chloro-5-methylphenoxy) butyric acid: LC-MS analysis: m+1 set peak (333). The results of 1H NMR analysis: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 7.61, d, 2H, (phenyl H, o to CO); δ 7.57, t, 1 N (phenyl N, R to CO); δ 7.44, t, 2H (phenyl N, m); δ 7.33, s, 1H (aryl H, o to CO); δ 7.14, s, 1H (aryl H, m); δ 3.87, t, 2H, (CH2α to O); δ 2.33, s, 3H, CH3); δ 1.81, t, 2H (CH2α to COOH); δ 1.49, p, 2H (mid CH2in the chain).13With NMR (d6-DMSO): 194.31, 173.83, 154.78, 139.80, 137.39, 133.17, 128.91, 128.84, 128.51, 127.55, 124.69, 115.57, 67.32, 29.37, 23.80, 20.03.

Possible way for the preparation of compounds F

[342] the Compound F can be prepared otherwise, using the method of acylation of aromatic compounds Friedel-:

[343] Using phenol, substituted appropriately, mix it with the corresponding bromoform use To2CO3as a basis, conduct the reaction product with the corresponding chloride aromatic acids in the presence of AlCl3; or take salicylic acid, substituted suitable clicks the zoom, and mix it with the corresponding bromoform using the K2CO3as the base. The product is transferred to the acid chloride SOCl2, which then reacts with benzene, substituted as appropriate, in the presence of AlCl3.

Example 8 - preparation of compound 174

[344] Compound 174 was prepared in three stages:

A. O-acetyl-5-chlorosalicylic acid

[345] 10 g (57,9 mmol) 5-chlorosalicylic acid was weighed in a 100-ml round bottom flask, then added acetic anhydride (12,8 ml, 115,9 mmol). Before adding concentrated sulfuric acid (2 drops), the mixture was stirred for 5 minutes. The reaction mixture was irrigated for 3 hours. The reaction was monitored by HPLC. The reaction mixture was cooled to room temperature and poured in chemical beaker containing 2 n HCl (200 ml) to precipitate the product. The product was collected by way of a vacuum filter. The purity was checked by HPLC, which allowed to detect the presence of impurities. In a 200-ml round bottom flask residue all night was stirred in water (150 ml). The insoluble solid was collected by way of a vacuum filter. The presence of impurities was checked by HPLC, which showed that the crude product no impurities. The product was dried overnight in vacuum, obtaining 12 g of o-acetyl-5-chlorosalicylic acid (56 mmol, Vyhod%).

C. O-acetyl-5-chlorosalicylic

[346] thionyl chloride (~100 ml) were placed in a 250 ml round bottom flask and stirred in an ice bath for 15 minutes. O-acetyl-5-chlorosalicylic acid (6.0 g of 27.9 mmol) was slowly added to the chilled thionyl chloride. For dissolving the acid in the reaction mixture was added DMF (2 drops). The reaction mixture was stirred overnight, after obtaining a homogeneous solution. The excess thionyl chloride drove in a vacuum. The remaining residue was dried in vacuum overnight.

C. 3-(N-2-hydroxy-5-chlorobenzoyl)aminopropionic acid

[347] (3-Alanine (2.5 g, of 28.0 mmol) was weighed in a 250 ml round bottom flask. To the flask was added methylene chloride (100 ml) and the mixture was stirred for 5 minutes. Then the flask was added drop by drop chlorotrimethylsilane (6,06 g, and 55.7 mmol). Under irrigation, the reaction mixture was heated for 15 minutes. The mixture was left to cool to room temperature and placed in an ice bath for 15 minutes. The triethylamine (8.5 g, 84,0 mmol) was slowly added to the cooled flask. O-Acetyl-5-chlorosalicylic (7.6 g of 27.9 mmol) was dissolved in methylene chloride (30 ml) and was added to the reaction mixture for 0.5 hours. The reaction mixture was stirred overnight, and left to warm to room temperature. The course of the reaction was confirmed by HPLC. The solvent is evaporated under vacuum. The remaining residue was mixed the 2 N. NaOH (~100 ml) for 2 hours and was slowly heated to 60°C. Then the solution was cooled to room temperature and was filtered by way of gravity-flow filtration. The filtrate was slowly acidified with concentrated HCl to precipitate formation. The crude product was collected when the pH of the mixture is equal to 6. The product was recrystallized using a mixture of Meon-N2O. Purity was checked by HPLC showed the presence of impurities. The product was repeatedly subjected to purification and recrystallization, haven't got net connection. The final product was stirred overnight in methylene chloride, collected by filtration method, and dried under vacuum overnight, getting a pink powder (3.98 g, 16.3 mmol, yield of 58.5%); melting point 181-183°C.; 1H-NMR (DMSO-d6) δ 2.47-2.58 (t, 2H), 3.44-3.54 (q, 2H), 6.93-6.98 (d, 1H), 7.39-7.44 (dd, 1H), 7.91-7.96 (d, 1H), 8.93-9.01 (t, 1H), 12.1-12.3 (s, 1H). The value of KF=1.615%. The results of the calculation of C10H10NO4Cl*0.2220H2O: C, 48.50; H, 4.25, N, 5.66. Found: C, 48.20; H, 4.03; N, 5.43.

Example 9 - Preparation of compounds 175-178

Connection 175-4-(2-benzyloxy-phenoxy)-butyric acid:

[346] In a 250 ml flask equipped with a reflux condenser and a magnetic stirrer, under inert atmosphere was added 2-benzyloxyphenol (8.0 g, 40 mmol), ethyl ester of 4-bromoethanol acid (5.7 ml, 40 mmol), potassium carbonate (7.2 g, 52 mmol), and ethanol (100 ml). Under irrigation, the reaction mixture was heated at premesis the Institute for 8 hours. Then the reaction mixture was cooled to room temperature and remove the insoluble by-product method by vacuum filtration. To the filtrate was added 2 N. aqueous sodium hydroxide solution (30 ml). This solution was heated to 50°C for 2 hours. Then the solution was cooled to room temperature, ethanol was removed under reduced pressure, and set the pH of the resulting solution is 9. The aqueous solution was washed with ethyl acetate (2×30 ml), and the remaining ethyl acetate was removed under reduced pressure. The solution was cooled to 0°C using an external ice bath and then acidified to pH=2 6 N. aqueous solution of hydrochloric acid. The precipitated product was collected by way of vacuum filtration and dried under vacuum. The product (7.2 g, 63%) was isolated as a white powder. 1H-NMR (400MHz, DMSO-d6): δ 12.0, s, 1H (COOH); δ 7.4, multiplet, 5H (benzyl aryl H); δ 7.0, multiplet, 2H (aryl H); δ 6.9, multiplet, 2H (aryl H); δ 5.0, s, 2H (benzyl CH3); δ 4.0, t, 2H (CH2α to phenoxy); δ 2.4, t, 2H (CH2α to COOH); δ 1.9, multiplet, 2H (remaining CH2group).

[347] Compound 176 - (4-Benzyloxy-phenoxy)acetic acid was purchased from Lancaster.

[348] Compound 177 - 11-(2-Benzyloxyphenyl)undecanoate acid:

[349] In a 250 ml Erlenmeyer flask was placed just ground potassium hydroxide (4,2 g, 74,91 mmol) and 100 ml of dimethylsulfoxide. Added benzyloxyphenol (5 g, 24,97 mmol) and methyl ester 11-bromoundecanoic acid (7 g, 25,07 mmol) and the mixture was stirred at room temperature overnight. Then added water (75 ml) and the solution was heated to 85°C. with stirring for three hours. The reaction mixture was cooled to room temperature and acidified with concentrated hydrochloric acid to pH=2. The acidified solution was cooled to 4°C for 2 hours, and then collected sediment way vacuum filtration. The product was recrystallized from a mixture of ethanol/water. Product (8,88 g, 93%) was isolated as light brown solid with a melting point of 62-63°C. Organic elementary analysis: found: 74.71 N 8.08%; C24H32O4requires at 74.97, H 8.39%;

[350] Compound 178 - 5-(4-benzyloxy-phenoxy)pentane acid:

[351] In a 500-ml flask with three necks, equipped with a reflux condenser, under inert atmosphere, was placed 4-benzyloxyphenol (30,64 g, 150 mmol), ethyl ester of 5-bromopentanoate acid (31,99 g, 150 mmol), potassium carbonate (22,80 g, 165 mmol), and 270 ml of 2-butanone. Under irrigation, the reaction mixture was heated for 23 hours, cooled and then diluted with ethyl acetate (150 ml) and was extracted on the background water (500 ml). The organic layer was washed with water (1×250 ml) and with brine (1×250 ml) and the solvent was removed under reduced pressure. The resulting oil was dried under vacuum in accordance with the s 4 days during which the formed white crystals. White crystals were dissolved in ethyl acetate (100 ml), washed with aqueous 1 N. a solution of sodium hydroxide (3×50 ml), and solvent was removed under reduced pressure. The resulting oil was dried under vacuum overnight, getting white crystals. The product was recrystallized from a mixture of 1:1 ethanol/water, collected way vacuum filtration and dried under vacuum. This product was used without further purification.

[352] In a 1-l round bottom flask equipped with a reflux condenser, was placed ethyl ester 5-(4-benzyloxy-phenoxy) pentanol acid (15,13 g, 46 mmol) and 2 N. aqueous sodium hydroxide solution (47 ml). The mixture was stirred for 30 minutes. Was added water (200 ml). The mixture was stirred for 20 minutes, then was heated under irrigation within 2 hours, forming a brown solution. By adding ice, the solution was rapidly cooled to room temperature. The cooled solution was acidified using 2n aqueous solution of hydrochloric acid (50 ml) and collect the resulting white precipitate way vacuum filtration, washed with water (2×100 ml), hexane (2×100 ml), and dried on vacuum overnight. The powder is finely grinded and washed with hexane (1×250 ml) and diethyl ether (1×250 ml)to give a white powder. In a 1-l beaker obtained powder was dissolved in a mixture of ethyl acetate (300 ml) and diethylether (200 ml). RA the solution was heated for 10 minutes was added methanol (5 ml), was heated for another 10 minutes, and then was filtered through zelany layer, receiving a transparent yellow solution. The product has led, slowly adding hexane. Collected the first batch of crystals by the method of filtration and to the stock solution was added hexane (200 ml). Then the solution was concentrated under reduced pressure to a volume of 400 ml and left for some time. The second portion of the crystals was collected by filtration and combined with the first. The product of 8.92 g, 65%) was isolated as a white crystalline substance with a melting point 127-128°C. Organic elementary analysis: found: 71.01 N 6.98%; C18H20O4requires 71.98; H 6.71%;

ConnectionHPLC retention TimeThe value of KFThe melting temperature, the interval of valuesCHNCCHNC NCHNFCHNF N
1755.93 min
176 5.54069.765.46
1765.54069.765.46
1779.19062-63At 74.978.3974.718.08
1786.120127-12871.986.7171.016.98

Example 10 - Oral delivery of PU'u [3-361 in solid form in the body of rats

[353] Used the original solution of PU'u [3-36] (80 mg/ml)prepared with deionized water (PU'u can be purchased at Bachem California Inc., TORRANCE, California).

[354] Approximately 0.08 mg/tablet (approximately 0.3 mg/kg) PU'u (approximately 1 ml) was added and was mixed with about 13.5 or 27 mg/tablet (50 or 100 mg/kg) svobodnenskoe or sodium salt of the connection carrier, as indicated below. The upper punch, lower punch and the mold hand press to produce tablets Carver 4350 with the standard sample in the form of capsules, production Natoli Engineering Company, Inc. (St. Charles, mo) were treated with stearate (0.1 per cent). Approximately of 13.58 mg or approximately 27,08 mg of the mixed powder was loaded into the mold and at a pressure of approximately 6894.74 kPa produced a mini-tablet in the form of granules. The resulting solid dosage form has approximate dimensions of a standard capsule 9 (diameter approximately 2,65 mm and a length of approximately 8,40 mm) for tablet 27,08 mg, and tablets of 13.58 mg diameter is approximately 2,65 mm and a length of approximately 4,20 mm

[355] Male rats Sprague Dawley (approximately 260 to 280 g) were fed all night and then were subjected to anesthesia using the standard method of CO2-inhalation for approximately 10-30 seconds, which resulted in a state of anesthesia in a time less than about 1 minute, preferably from about 10 to 30 seconds.

[356] Used a dosing tube for oral administration. The metering tube was inserted to rats in her mouth and gently penetrated into the pharynx, and esophagus of rats approximately 8-15 cm, depending on the weight of the rat (in the General case, at approximately 11 cm). Solid dosage form was introduced into the distal esophagus and/or guludo is, pushing on the plunger of the dosing tube to oral input.

[357] blood Samples were taken retro-orbital method usually after 0, 15, 30, 60 and 90 minutes. Concentration DYY serum quantitatively determined using radioimmunoassay examination on the content of PU'u [3-36] (Catalog #RK-059-02 from Phoenix Pharmaceuticals, Inc., Belmont, California). The results obtained in animals in each group were averaged for each time point. The maximum value of these averages (i.e., the average maximum concentration of PU'u [3-36] in serum ± standard deviation (SB)) below.

Table 1
Oral administration of PU'u [3-361 in the body of rats
Connection-mediaRoute of administrationDose compound (mg/kg)Dose of PU'u [3-36] (mg/kg)Average maximum content of PU'u in serum (PG/ml) ± CO
23 - salt sodiumOral, solid dose, 1 tablet per animal1000.3427.4±258.7
121 - salt sodiumthe Bolsheviks, solid dose, 1 tablet per animal1000.3897.1±257.3
121 free acidOral, solid dose, 1 tablet per animal500.3161.7±148.5
174 - salt sodiumOral, solid dose, 1 tablet per animal-1000.3675±427.1
174 free acidOral, solid dose, 1 tablet per animal1000.30

Example 11 - Oral delivery PUP-361 in liquid form in the body of rats

[358] the Dosing solutions for oral input connection carrier and peptide YY residues 3-36 (PU'u [3-36]) (available from Bachem California Inc. of Torrance, Calif.) in deionized water were prepared as follows.

[359] the Original solution of PU'u [3-36] (80 mg/ml) was prepared using deionized water. There were prepared compositions for oral input, containing 200 mg/kg connection carrier and 0.3 mg/kg of PU'u in aqueous solution. A solution of compound 23 th is tableware, adding one equivalent of sodium hydroxide to the transfer agent of the carrier in the form of the free acid to its sodium salt.

[360] Male rats Sprague-Dawley weighing between 240-320 d before experiments were not fed for a maximum of 24 hours and before the introduction of the test product was administered ketamine (44 mg/kg) and Chorazin (1.5 mg/kg) by intramuscular injection. Then, shot the animal orally was administered the test compound. A group of five animals was administered to one of the dosing solutions. For oral input, 11 cm French catheter Rusch 8 attached to a 1 ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which is then wiped dry. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors. The dosing solution was administered by pressing the plunger of the syringe.

[361] blood Samples were collected serially from the tail artery or by puncture of the heart, usually after 0, 15, 30, 45, 60 and 90 minutes. The concentration of PU'u serum quantitatively determined using radioimmunoassay examination on the content of PU'u [3-36] (Catalog #RK-059-02 from Phoenix Pharmaceuticals, Inc., Belmont, California). The results obtained in animals in each group were averaged for each time point.

The maximum value of these averages (i.e., the average maximum concentration of PU'u [3-36] in serum ± standard deviation (is)) are shown below in table 2. When animals orally was administered only PU'u [3-36], the essential content of PU'u [3-36] in the blood is not found.

Table 2
Oral administration PUP-361 (liquid) in the body of rats
ConnectionRoute of administrationDose compound (mg/kg)Dose of PU'u [3-36] (mg/kg)The average maximum concentration of PU'u in serum (PG/ml) ± CO
23Oral administration (liquid dose)2000.3788.198±50.59
151Oral administration (liquid dose)2000.3801.96±290.61
158Oral administration (liquid dose)200-0.31065±75.352
160Oral administration (liquid dose)2000.330.39±306.29
160Oral administration (liquid dose)2000.3631.96±316.16
160Oral administration (liquid dose)2000.3705.106±75.906
161Oral administration (liquid dose)2000.3340.95±228.946
174
Oral administration (liquid
dose)
2000.31262.26±313.58

Example 12 - Oral delivery of recombinant human insulin in the rat organism

[362] Insulin (human recombinant) was purchased from ICN Biomedicals (Aurora, Ohio) in the form of bulk powder. For the preparation of initial solutions insulin was dissolved in deionized water (pH~6,5), obtaining a concentration of 15 mg/ml To use the original solutions were kept frozen at -20°C in 1.0-ml aliquot. In order to obtain the final concentration of the carrier in dosing solutions of 200 mg/ml, the connection carrier dissolve the Yali and deionized water. The reagent carrier in the form of the free acid was transferred into the sodium salt by adding one equivalent of sodium hydroxide. The solutions were shaken, were treated with ultrasound and was heated and, if necessary, once again, was added sodium hydroxide in ml-quantities to achieve a uniform solubility. the pH of the solutions was established in the range of 3.5 to 8.5 by adding or perchloric acid, or sodium hydroxide. Then, to obtain a final concentration of 0.5 mg/ml of the original solution of insulin (usually 66,7 ml) was added to a solution of the reagent carrier. After dilution and addition of the drug solution was brought to final volume by adding deionized water.

[363] Oral method in male rats were injected or insulin, or insulin in combination with a reagent carrier Emisphere. Usually before the introduction of the rats were not fed for a period of 18-24 hours. For the introduction of French catheter Rusch 8 was shortened to 11 cm in length and adapted for use with a syringe 1 ml Syringe was filled with the dosing solution and the catheter dry wiping, removing excess solution. The catheter was inserted into the mouth of the rat and directed into the esophagus (10.0 cm). The dosing solution was injected by pressure on the plunger of the syringe, holding the rat in the standing position.

Sampling and processing of samples: insulin

[364] When sampling blood directly to each of selection is and rats quickly (~10 sec) were exposed to the effect of carbon dioxide, until then, until they fell into a state of prostration. Blood collection 77-mm capillary tube was inserted into the retro-orbital cavity. Typically, blood samples were taken before injection (time 0) and after 15, 30, 45, and 60 minutes after injection. Samples were collected in tubes CAPIJECT® (Terumo Corporation, Tokyo, Japan)containing activator of blood coagulation (red cap, spacer tubes for serum). The samples were left to roll for ~20 minutes at 4°C. After coagulation, in order to separate the serum, samples were centrifuged at 10,000 turnover/min for 4 minutes at 6°C. the Serum was collected in Eppendorf tube and cooled at -20°C prior to analysis.

Sampling and processing of samples: glucose in whole blood

[365] in order to determine the pharmacodynamic response to measurement of glucose in whole blood after administration of insulin or insulin reagent carrier used hand-held glucometer (OneTouch Ultra, LifeScan® (Johnson & Johnson, new Brunswick, new Jersey)). Samples were collected, or from the retro-orbital cavity (see the Sampling and processing of samples: insulin) or from the tail artery (i.e. by cutting the tail). When cutting the tail tip of the tail cut off with a scalpel approximately 5 mm After discarding the first drops of blood, a small break (~5-10 μl) was touched to the test strip glucometer (OneTouch Ultra, LifeScan) and the device appeared on asana of glucose in the blood. Each subsequent selection, a blood clot formed at the tip of the tail, was destroyed and robbed of a fresh sample. In General, samples were taken before injection (time 0) and after 15, 30, 45, and 60 minutes after injection.

Table 3
Oral administration of insulin (liquid dose) in the body of rats.
ConnectionRoute of administrationThe dose of a compound of the carrier (mg/kg)Insulin dose (mg/kg)The maximum % fall in glucose ± WITH (control)
24Oral administration (liquid dose)2000.5-14.73±17.64
25Oral administration (liquid dose)2000.5-14.81±12.99
26Oral administration (liquid dose)2000.5-25.93±at 14.86
27P is realnoe introduction (liquid dose) 2000.5-25.40±at 30.61
28Oral administration (liquid dose)2000.5-11.41±18.92
29Oral administration (liquid dose)200-0.5-29.25±6.97
140Oral administration (liquid dose)1001Cmax=81.16±114.98 mkme/ml
141Oral administration (liquid dose)1001Cmax=204.05±60.88 mkme/ml
142Oral administration (liquid dose)1001Cmax=118.16±72.75 mkme/ml
145Introduction through the colon500.1Cmax=15.03±7.80, mkme/ml
145 Oral administration (liquid dose)1001Cmax=3.92±5.62, mkme/ml

160Oral administration (liquid dose)2000.5Cmax=74±7.5 mkme/ml
165Oral administration (liquid dose)2000.5-33.0
166Oral administration (liquid dose)2000.5-5.7
167Oral administration (liquid dose)2000.5-21.2
167Oral administration (liquid dose)2000.5-17.7
167Oral administration (liquid dose)2000.5-26.2
167Oral administration (liquid dose)2000.5-17.8
167Oral administration (liquid dose)2000.5-22.7

Example 13 - Human zinc insulin oral delivery

[366] the Compositions of the connection carrier and the human zinc insulin for oral administration (at least 26 IU/mg, you can buy in Calbiochem - Novabiochem Corp., La JOLLA, CA) were prepared in deionized water. 500 mg of the connection carrier was added to 1.5 ml of water. Free acid included in the composition of the medium was transferred into the sodium salt by stirring the resulting solution and adding one equivalent of sodium hydroxide. The solution was shaken, and then heated (approximately 37°C) and treated with ultrasound. the pH was set in the range of about 7-8,5 using NaOH or HCl. To achieve a uniform solubility, if necessary, was added an additional amount of NaOH, and the pH was again set in the range of from about 7 to 8.5. Then water was brought the total amount of up to about 2.4 ml and shook. Approximately 1.25 mg of insulin from the original races is the thief of insulin (15 mg/ml, prepared by mixing 0,5409 g of insulin and 18 ml of deionized water, set pH=8,15 using HCl and NaOH and, to obtain a transparent solution, using 40 ml of concentrated HCl, 25 ml 10h NaOH and 50 ml 1N NaOH) was added to the solution and mixed by inverting. See the final dose of the connection carrier, insulin and the volume of the doses.

[367] Male rats Sprague-Dawley, weighing approximately 200-250 g, were not fed for 24 hours and was administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to the introduction and again, if you want to save the anesthesia. A group of five animals was administered to one of the dosing solutions. For oral input, 11 cm French catheter Rusch 8 attached to a 1 ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which is then wiped dry. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors. The dosing solution was administered by pressing the plunger of the syringe.

[368] blood Samples were collected serially from the tail artery, generally after 15, 30, 60, 120 and 180 minutes. Insulin levels in serum were determined using a test kit Insulin ELISA kit (kit # DSL-10-1600 from Diagnostic Systems Laboratories, Inc., Webster, Texas), correcting the standard Protocol to optimize the sensitivity and the linear region of the calibration curve for volumes and concentrations of the Rob, used in this Protocol. The concentration of human insulin in serum (mked/ml) was measured for each time point for each of the five animals in each group. Five values for each time point were averaged and the results were plotted on the graph: the insulin concentration - time.

(Previous experiments showed no measurable levels of human insulin after its introduction without reagent carrier). The maximum (peak) and area under the curve (PPC) is shown below in table 4. For % change relative to baseline for Blood Glucose the ONE TOUCH® (Life Scan, Johnson & Johnson, new Brunswick, new Jersey).

tr>
Table 4
Insulin oral delivery
Connection-mediaThe dose of a compound of the carrier(mg/kg)Insulin dose (mg/kg)Volumetric dose (ml/kg)Cmax (glucose)(µU/ml)ACCGlucose (% control)
1232000.50107.37440
1252000.5098.37687.5
1232000.50100.37447.5
1152000.5083.33232.5
1162000.5089.53292.5
1182000.5090.54327.5
1242000.5087.8RUB 1,582 .5
1342000.5081.53817.5
1362000.5091.54507.5
1382000.5093.46907.5
1242000.5059.9112.5
1522000.5-29.3%
1532000.5 -7.1%
1542000.5-7.9%
1592000.5-6.6%
1592000.59.1-36.5%

Example 14 - Insulin - delivery through the lungs

[368] Were prepared batched compositions connection-media and human insulin in the water. In the General case to 1.5 mg of the connection carrier was added deionized water, bringing the volume to 1.0 ml, and was dissolved in the solution. Used or sodium salt of the connection carrier, or the free acid was transferred into the sodium salt by stirring the resulting solution, adding one equivalent of sodium hydroxide (10 n) and dilution water. The solution was shaken, and then heated (approximately 37°C) and treated with ultrasound. the pH was determined from approximately of 7.0 to 8.5 with NaO or HCl. To the solution was added 75 μl of the original solution of human insulin (2 mg/ml). (The original solution was prepared as follows. To 0.02 g of insulin was added 3 ml of HCl solution in deionized water with a pH of 3.0. the pH of the resulting solution was made using HCl and NaOH to values below 3.0 (about 2.6) up until the solution became transparent. Then the pH was brought to 7.6 using NaOH and HCl. The final volume was brought to 10 ml with deionized water with a pH of 7.5. The final pH to 7.59). Then add water, bringing the total volume to 2.0 ml, and the solution is then gently turn it over several times. According to the report introduction, the solution can be used immediately after preparation, or in another example implementation, before the introduction it can be placed in a water bath with a temperature of 37°C for one hour. The final dose of the connection carrier, the insulin dose and the volume of doses below in table 4.

[369] Typical protocols introduction and sampling are the following. Male rats Sprague-Dawley, weighing between 200-250 g, were not fed within 24 hours and 15 minutes before the injection was administered ketamine (44 mg/kg) and chlorpromazine (3.0 mg/kg) and, if necessary, to maintain anesthesia, introduced them again (using the same amount of ketamine and 1.5 mg/kg of chlorpromazine). Usually a group of five animals was administered to one of the dosing solutions. The control group of five animals were injected insulin is telno. Tracheal dropper for rodents, equipped with a light source (can be purchased in Perm Century, Inc., Pittsburgh, Pennsylvania), was filled with the dosing solution and inserted into the throat so that the needle has entered the trachea (visually confirmed). The dosing solution was injected by pressure of the piston.

[370] blood Samples from each animal were collected serially from the tail artery, generally after 5, 15, 30, 60 and 120 minutes after injection. Insulin levels in serum were determined using a test kit Insulin ELISA kit (kit # DSL-10-1600 from Diagnostic Systems Laboratories, Inc., Webster, Texas), correcting the standard Protocol to optimize the sensitivity and the linear region of the calibration curve for volumes and concentrations of the samples used in this Protocol. The concentration of insulin in serum (mked/ml) was measured for each time point for each of the five animals in each group. Five values for each time point were averaged and the results were plotted on the graph: the insulin concentration - time. The ratio of the area under the curve (CPD) for the test group relative to the square of the control group are given below. The ratio of maximum concentration of insulin in serum (Cmax) in the test group relative to the maximum concentration in the control group also listed below.

Table 5
The delivery of insulin through the lungs
Connection-mediaVolumetric dose (ml/kg)The dose of a compound of the carrier (mg/kg)Insulin dose (mg/kg)Cmax
1740.4160.0318.36±19.18

Example 15 - delivery of oral heparin and through the colon

[371] Were prepared dosing solutions for oral administration and injection through the colon (CPD)that contains the connection carrier and heparin sodium USP 25% aqueous solution of propylene glycol. Used the sodium salt of this compound. In the General case, the connection carrier and heparin in the form of dry powders (approximately 166-182 IU/mg) was mixed with shaking. This dry mixture was dissolved in 25% (by volume) aqueous solution of propylene glycol, were shaken and placed in a device for ultrasonic treatment (approximately 37°C). the pH was set to about 7 (6.5 to 8.5), using an aqueous solution of NaOH (2 BC). The dosing solution was treated with ultrasound, obtaining a clear solution. Drove the final volume to 3.0 ml of Koh is CNA the dose of a compound of the carrier, heparin dose and volume doses are shown in table 6.

[372] Used the following typical protocols introduction and sampling. Male rats Sprague-Dawley weighing 275-350 g, not fed within 24 hours and obezbolivatmi of ketamine hydrochloride (88 mg/kg) by intramuscular injection immediately before injection. A group of five animals was administered to one of the dosing solutions. For oral input 11 cm French catheter Rusch 8 was attached to the syringe 1 ml pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which is then wiped dry. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors. The solution was injected by pressing the plunger of the syringe. When you enter through the large intestine (CPD) 7.5 cm French catheter Rusch 8 was attached to the syringe 1 ml pipette tip. Dosing catheter was inserted into the colon through the anus up until the tube has not ceased to be visible. The dosing solution was slowly introduced into the large intestine.

[373] Citrate blood samples were taken by puncture method heart, pre introducing ketamine (88 mg/kg), usually through 0,25, 0,5, 1,0 and 1,5 hours. The activity of heparin was determined using time partial activated thromboplastin (VCAT) in accordance with the way Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods, Philadelphia, PA, W.B. Saunders (1979). According to the preliminary and the studies, the value of the base line of approximately 20 seconds. The results obtained in the study of five rats in each group were averaged for each time point. The obtained maximum below in table 6.

52.40±21.54
Table 6
Oral/vnutripoliticheskaya shipping heparin
Connection-mediaMethod of introductionVolumetric dose (ml/kg)Dose compound (mg/kg)Heparin dose (mg/kg)Average maximum VCAT (sec) ± CO)pH
114VTK1502542.90±8.707.61
140VTK1502523.49±6.127.67
141VTK150257.62
143VTK15025114.69 last±121.627.18
145VTK15025134.42±99.036.93
151Oral3300100252.09±107.13
151
VTK150252.36±1.27 (antifactor
CA)
7.06
151VTK125253.39±3.07 (artifactory)7.23
160VTK15025 131+154 (Tmax=90 min)

Example 16 - the delivery of parathyroid hormone (PTH 1-34) - Oral/vnutripoliticheskaya shipping

[374] there Were prepared solutions of the connection carrier and the remnants of the human parathyroid hormone 1-34 (PTH) in water for oral administration and/or insertion through the colon. Used the sodium salt of the compound of the media. Usually a solution of this compound was prepared in water and stirred, adding one equivalent of sodium hydroxide (1.0 n), obtaining the sodium salt. Prepared final dosing solutions by mixing the compounds with the initial solution PTH (PTH were obtained from Eli Lilly and Co., Indianapolis, Indiana (typically having a concentration of 5 mg PTH/ml) and diluting to the desired volume (usually 3.0 ml). The target compound, PTH and volume number of doses below in table 7.

[375] Used the following typical protocols introduction and sampling. Male rats Sprague-Dawley, weighing 200-250 g, were not fed for 24 hours and was administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to injection. A group of five rats were administered one of the dosing solutions. For oral input 11 cm French catheter Rusch 8 was attached to the syringe 1 ml pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which is then wiped to the ear. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors of rats. The solution was injected by pressing the plunger of the syringe. When you enter through the large intestine (CPD) 7.5 cm French catheter Rusch 8 was attached to the syringe 1 ml pipette tip Eppendorf. The syringe was filled with dosing solution by drawing the solution through the catheter tube. Catheter tube is wiped dry. The pipette tip smeared with gel (K-Y jelly, avoiding contact with eye tube, and the tube was inserted into the colon until then, until it was visible. The solution was injected by pressing the plunger of the syringe, and the tube was removed.

[376] blood Samples were collected serially from the tail artery, in the General case of 0, 15, 30, 45, 60 and 90 minute oral introduction and 0, 10, 20, 30, 60 and 90 minutes when introduced through the colon. The concentration of PTH in serum quantitatively determined using a radioimmunoassay kit for the analysis of PTH content (Kit # RIK 6101 from Peninsula Laboratories, Inc. San Carlos, California). Preliminary studies show the value of the base line is approximately zero. The results of the blood test five rats in each group were averaged for each time point. The maximum value is shown below in table 7.

Table 7
Shipping law is the body of rats by oral means or through the colon
Connection-mediaRoute of administrationVolumetric dose (ml/kg)Dose compound (mg/kg)The dose of PTH(m kg/kg)The average maximum concentration [PTH] in serum (PG/ml) ± COpH
113Oral1100200780.77±439.928.18
113Oral110020053.51±39.558.09
114Oral1100200135.78±136.978.41

Example 17 - Interferon - Oral delivery

[377] In deionized water were prepared with the dosing solutions of the connection carrier and interferon of alfacon-1 (IFN) (can be purchased in the form of Infergen® InterMune, Inc. Brisbane, Calif.). Free acid that is included with soy is inane carrier, translated into the sodium salt by adding one equivalent of sodium hydroxide. Usually prepared solution of the connection carrier in water and stirred, adding one equivalent of sodium hydroxide (1.0 n) to obtain the sodium salt. This mixture was shaken and placed in a device for ultrasonic treatment (approximately 37°C). the pH was set from about 7.0 to 8.5 by adding an aqueous solution of NaOH. To obtain a homogeneous suspension or solution, and the mixture was shaken, and, if necessary, used the device for ultrasonic treatment and heating. To achieve a homogeneous solubility, if necessary, was added an additional amount of NaOH, and the pH was again installed in the region of from 7.0 to 8.5. Solution connect the carrier was mixed with the initial solution DETAILS (approximately 22,0-27.5 mg/ml in phosphate buffered saline solution) and diluted to the desired volume (usually 3.0 ml). The final dose of the connection carrier and DETAILS and dosage amounts are presented in table 8.

[378] With the introduction and sampling is usually used following protocols. Male rats Sprague-Dawley, weighing approximately 200-250 g, were not fed for 24 hours and was administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to entry and, if necessary, to maintain anesthesia, introduced them again. A group of five animals was administered to one of the dosing process is economical. 11 see French catheter Rusch 8 was attached to the syringe 1 ml pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which is then wiped dry. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors. The dosing solution was administered by pressing the plunger of the syringe.

[379] blood Samples were collected serially from the tail artery, usually after 0, 15, 30, 45, 60 and 90 minutes. The concentration of INF quantitatively determined using an immunological kit with cytogram for determination of human alpha-INF (directory # CNS from Biosource International, Camarillo, California). According to preliminary studies of baseline values was equal to approximately zero. The results obtained with blood samples of animals from each group were averaged for each time point. The maximum of these values (for example, the average maximum concentration of IFN in serum) are shown below in table 8.

Table 8
Interferon - Oral delivery
Connection-mediaThe dose of a compound of the carrier (mg/kg)Dose INF (mg/kg)Volumetric dose (ml/kg)pH
141200110.73±0.448.29
147200111.27±0.608.45
174200110.5±0.57
174200110.18±0.17
174200113.96±2.72
1742001117.4±9.12

Example 18 - Oral delivery of calcitonin salmon (LKT)

[380] there Were prepared compositions for oral input connection carrier and calcitonin salmon (LKT) in water. Usually 450 mg of the connection carrier was added to 2.0 ml of water. Used or sodium salt of the compounds, or the free acid was transferred into the sodium salt by stirring the resulting solution, adding one equivalent of sodium hydroxide (1.0 n) and dilution water. The solution was shaken, and then heated (approximately 37°C) and treated with ultrasound. Established a pH of about 7 (6,do 8,5), adding NaOH or HCl. 90 g LKT from the original solution was added to the solution. Then water brought the total to about 3.0 ml (varies depending on the solubility of the connection carrier). The final dose of the connection carrier, the dose of LKT and volume doses below in table 9.

[381] Male rats Sprague-Dawley, weighing approximately 200-250 g, were not fed for 24 hours and was administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to injection. A group of five animals was administered to one of the dosing solutions. For oral administration 11 cm French catheter Rusch 8 was attached to the syringe 1 ml pipette tip. The syringe was filled with dosing solution by drawing the solution through Keter, which is then wiped dry. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors of rats. The dosing solution was administered by pressing the plunger of the syringe.

[382] blood Samples were collected serially from the tail artery, usually after 0, 10, 20, 30, 60 and 90 minutes. The concentration of LKT in serum was determined by testing using EIA kit (Kit # EIAS-6003 from Peninsula Laboratories, Inc., San Carlos, California), correcting the standard Protocol from the kit as follows: maintained with a mixture of 50:1 peptide: antibody for 2 hours with shaking in the dark, washed the Cup, added serum and biotinylated peptide was diluted to 4 ml of buffer, and the darkness shook all night. Indicators were established in accordance with baseline values obtained at time=0. The results of the blood test five rats in each group were averaged for each time point. The maximum listed in the following table 9.

Table 9
Oral delivery of calcitonin salmon (LKT)
Connection-mediaVolumetric dose(ml/kg)Dose compound (mg/kg)Dose LCG (mg/kg)The average maximum concentration of LKT in serum (PG/ml±) (SE)
174150301182.83±184.82
174150301198.21±205.15
17415030170.81±118.47

Example 19 - delivery of recombinant human growth hormone (rcgr) oral means or through the colon

[383] Were sentence is Owlery solutions of the connection carrier and rcgr in phosphate buffer for oral input and/or input through the colon (rcgr can be purchased at Novartis, Basel, Switzerland). The sodium salt of the connection carrier was obtained through reaction of the free acid with one equivalent of sodium hydroxide. The final dosing solutions were prepared by mixing the compounds with the initial solution rchr (15 mg rchr/ml) and diluting to the desired volume (usually 3.0 ml). A dosed quantity of connections and rcgr below in table 10.

[384] Used the following typical protocols introduction and sampling. Male rats Sprague-Dawley, weighing 200-250 g, were not fed for 24 hours and was administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to injection. A group of five rats were administered one of the dosing solutions. For oral input 11 cm French catheter Rusch 8 was attached to the syringe 1 ml pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which is then wiped dry. The catheter was placed in the esophagus, leaving 1 cm of the tube behind the incisors of rats. The solution was injected by pressing the plunger of the syringe. When you enter through the large intestine (CPD) 7.5 cm tube catheter Rusch 8 (French 8 or 6) was attached to the syringe 1 ml pipette tip Eppendorf. The syringe was filled with dosing solution by drawing the solution through the catheter tube. Catheter tube is wiped dry. The pipette tip smeared with gel (K-Y jelly, avoiding contact with eye tube, and the tube insert the Yali in the colon through the anus until until it becomes not visible. The solution was injected by pressing the plunger of the syringe, and the tube was removed.

[385] blood Samples were collected serially from the tail artery or retro-orbital cavity, usually after 0, 15, 30, 45, 60 and 90 minute oral introduction and 0, 10, 20, 30, 60 and 90 minutes at vnutricletocnam introduction. Samples were collected in tubes CAPIJECT® (Terumo Corporation, Tokyo, Japan)containing activator of coagulation (red cap, spacer tubes for serum). The samples were left to roll for ~20 min at 4°C. the Concentration rcgr serum quantitatively determined using a test kit for immunological analysis rchr (Kit#K1F4015 from Genzyme Corporation Inc., Cambridge, Massachusetts). Five samples for each time period combined. According to preliminary studies, the baseline values approximately equal to zero.

[386] the Maximum concentration for each group are presented below in table 10.

Table 10
Oral/vnutripoliticheskaya shipping rcgr in the body of rats
Connection-mediaRoute of administrationVolumetric dose (ml/kg)Dose compound (mg/kg) Dose rchr (mg/kg)The average maximum concentration rcgr in serum (ng/ml)
160Oral12003-
161Oral120031.033 (±2.31)(Tmax=15 min)
174Oral1200357.42

All publications, references, patents, published patent applications mentioned herein are decorated by reference.

1. A compound selected from:


and their pharmaceutically acceptable salts.

2. Pharmaceutical composition for delivery of biologically active substances, containing:
(A) at least one biologically active substance, selected from a peptide YY [PYY], insulin and parathyroid hormone; and
(B) an effective amount of a compound selected from










and their pharmaceutically acceptable salts.

3. The pharmaceutical composition according to claim 2, characterized in that the biologically active substance is a human insulin-zinc.

4. The pharmaceutical composition according to claim 2, characterized in that the biologically active substance is a PYY [3-36].

5. The pharmaceutical composition according to claim 2, characterized in that the biologically active substance is a human parathyroid hormone (PTH-1-34).

6. The method of introduction of biologically active substances, selected from a peptide YY [PYY], insulin and parathyroid hormone, an animal that needs to be specified substance, comprising oral administration of a specified animal the pharmaceutical composition according to claim 2.

7. A compound selected from the following:






and their pharmaceutically acceptable salts.

8. Pharmaceutical composition for delivery of biological the key active substances, contains:
(A) at least one biologically active substance, selected from a peptide YY [PYY], insulin, heparin and interferon; and
(B) an effective amount of a compound according to claim 7.

9. The pharmaceutical composition of claim 8, characterized in that the biologically active substance is interferon of alfacon-1.

10. The pharmaceutical composition of claim 8, characterized in that the biologically active substance is a human recombinant insulin.

11. The pharmaceutical composition of claim 8, characterized in that the biologically active substance is heparin.

12. The pharmaceutical composition of claim 8, characterized in that the biologically active substance is a PYY [3-36].

13. The method of introduction of biologically active substances, selected from a peptide YY [PYY], insulin, heparin and interferon, an animal that needs to be specified substance, comprising oral administration of a specified animal the pharmaceutical composition of claim 8.

14. Connection, including:

and its pharmaceutical acceptable salts.

15. Pharmaceutical composition for delivery of biologically active substances, containing:
(A) insulin and
(B) effective number of connections 14.

16. The pharmaceutical composition according to item 15, distinguish the different topics the specified insulin is a recombinant human insulin.

17. Method of insulin administration to an animal that needs to be given insulin, comprising oral administration of a specified animal pharmaceutical composition according to item 15.



 

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SUBSTANCE: invention relates to novel compound of salvianolic acid L with general formula (I) , to its pharmaceutically acceptable salts and hydrolysable ethers, with compound of salvianolic acid L having one pair of protons of trans-form double bond and one proton of single-substituted double bond; and compound of salvianolic acid L is intended for treating cardiovascular disease, capture of free radicals and/or prevention of excessive oxidation.

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< / BR>
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9 cl, 3 dwg, 2 tbl, 34 ex

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24 cl, 89 ex

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23 cl, 7 tbl, 1 dwg

FIELD: organic chemistry, medicine, pharmacy, cosmetology.

SUBSTANCE: invention relates to novel biphenylmethylthiazolidinedions of the general formula (I): , their salts, and to their optical and geometrical isomers possessing agonistic activity with respect to PPARγ receptors, to pharmaceutical and cosmetic compositions based on thereof, and to their using for preparing composition used in treatment of different cutaneous diseases. In compound of the formula (I) R1 means radical of the following formula (a): or (b): ; R2 and R3 mean hydrogen atom; X means binding groups showing the following structures: -CH2-N(R8)-CO-, -N(R8)-CO-N(R9)- that can be read from left to right or vice versa; R4 means phenyl substituted with group R10, pyrrolyl, naphthyl, biphenyl, indenyl, benzothienyl and all these groups can be mono- or di-substituted with group R11 and/or R12, group -(CH2)n-(CO)qR13, adamantyl, cyclopentylethyl, group -(CH2)n-O-R13; R5 means hydroxyl or alkoxyl with 1-19 carbon atoms; R6 means group -OR14. Values R8, R9, R10, R11, R12, R13, n and q are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

25 cl, 2 dwg, 37 ex

FIELD: organic chemistry, amino acids, chemical technology.

SUBSTANCE: invention relates to a new method for preparing novel derivatives of phenylalanine. Also, invention relates to new compounds used as intermediate substances used in this method. Invention proposes a method for synthesis of compounds of the formula (I) wherein X1 means halogen atom; X2 means halogen atom; Q means group of the formula -CH2- or -(CH2)2-; Y represents lower alkyl group, or its pharmaceutically acceptable salt that shows the excellent inhibitory effect against cellular adhesion mediated with integrin α4, and a semi-finished product used in this method. Proposed method provides the possibility for preparing compound of the formula (I) or its pharmaceutically acceptable salt of the high purity in combination with the high yield and small consumptions.

EFFECT: improved preparing method.

13 cl, 8 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

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