Antiinflammatory medications

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 3-aminocaprolactam of formula (I): , where X represents -CO-R1 or -SO2-R2, R1 represents alkyl (with the exception of 5-methylheptanyl and 6-methylheptanyl, where radical R1 is bonded to carbonyl in position 1), halogenalkyl, alkoxy (with the exception of tret-butyloxy), alkenyl, alkinyl or alkylamino radical from 4-20 carbon atoms (for example, from 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms) and R2 is alkyl radical from 4-20 carbon atoms (for example, from 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms); or to its pharmacologically acceptable salt. Invention also relates to application and pharmacological composition, which has anti-inflammatory activity, based on said compounds.

EFFECT: obtaining new compounds and based on them pharmacological composition, which can be applied for obtaining medications for treatment, relief or prevention of inflammatory disease symptoms.

57 cl, 62 ex

 

The invention relates to the use of derivatives of 3-aminocaproate for manufacturing a medicinal product intended for the prevention or treatment of inflammatory disorders.

Inflammation is an important component of physiological defenses. However, it becomes clearer that junk over time and the spread of inflammatory reactions play a role in a wide range of diseases, including diseases with obvious leukocyte component (such as autoimmune diseases, asthma or atherosclerosis), but also diseases that have traditionally been considered to be associated with leukocytes (such as osteoporosis or Alzheimer's disease).

Chemokines are a large family of signaling molecules homologous to interleukin-8, which is involved in the regulation of movement of cells in physiological and pathological conditions. When more than 50 ligands and 20 receptors involved in the control of chemokine signals, the system has the required density information to access the cells in immune complex regulatory processes from the bone marrow to the periphery, then back through the secondary lymphoid organs. However, the complexity of the chemokine system was initially hampered the search for new pharmacological approaches to modulating the inflammatory reaction is s through blockade of chemokine receptors. Was difficult to determine what chemokinesis receptor(s) should inhibit for a therapeutic effect in this inflammatory disease.

It was later described family of funds, which block the transmission of signals simultaneously a wide range of chemokines (Reckless et al., Biochem J. (1999) 340:803-811). It was found that the first such tool, peptide, called "peptide 3", inhibits the migration of leukocytes caused by 5 different chemokines, at the same time leaving unchanged migration in response to other chemoattractant (such as fMLP or TGF-beta). This peptide and its analogues, such as NR58-3.14.3 (i.e. Sequence ID No.1jointly referred to as "Inhibitors of chemokines broad spectrum" (BSCI). Subsequently, Grainger et al., Biochem. Pharm. 65 (2003) 1027-1034, showed that the BSCI have potentially beneficial anti-inflammatory activity for a number of diseases in animal models. Interestingly, simultaneous blockade of multiple chemokines are not obviously associated with acute or chronic toxicity, suggesting that this approach may be a useful strategy for the development of new anti-inflammatory drugs with advantages similar to steroids, but with reduced side effects.

However, the peptides and peptide derivatives, so the e as NR58-3.14.3, may not be optimal for use in vivo. Their synthesis is quite expensive, and they have a relatively unfavorable pharmacokinetic and pharmacodynamic properties. For example, NR58-3.14.3 biologically unavailable when administered orally and after intravenous injection is derived from blood plasma with half-life less than 30 minutes

Two parallel strategies were adopted to identify new drugs that retain the anti-inflammatory properties of peptide 3 and NR58-3.14.3, but have superior characteristics for their use as pharmaceuticals. First, they developed a series of peptide analogs, some of which have a longer elimination half-life than NR58-3.14.3, and the synthesis of which is considerably cheaper. Secondly, conducted a detailed analysis patterns: activity of peptides to identify key pharmacophores and design not small peptide structures that preserve the useful properties of the original peptide.

This second approach has identified several structurally distinct series of compounds that retain anti-inflammatory properties of the peptides, including the 16-amino and 16-aminoaniline derived alkaloid yohimbine, as well as a series of N-substituted 3-aminoglutethimide (Reference: Fox et al., J Med Chem 45(2002) 360-370: WO 99/12968 and WO 00/42071). All these compounds predstavljaetsja inhibitors of chemokines broad spectrum that retain the selectivity before not the chemokine chemoattractants, and it was shown that the number of blocks of acute inflammation in vivo.

The most active and selective of these compounds was (S)-3-(undec-10-enoyl)aminoglutaramic (NR58,4), which inhibited induced chemokine migration in vitro when ED505 nm. However, further research revealed that aminoglutethimide ring was susceptible to enzymatic ring opening in the serum. Therefore, for some applications (for example, being treated the inflammation is chronic, for example, autoimmune diseases), these compounds can have optimal properties, and more stable compound with similar anti-inflammatory properties may have advantages.

With the aim to identify such stable analogues were tested derivatives (S)-3-(undec-10-enoyl)aminoglutethimide on their stability in serum. One such compound, 6-deoxo analogue (S)-3-(undec-10-enoyl)tetrahydropyridine-2-it is completely stable in human serum for at least 7 days at 37°C, but has a significantly reduced activity compared to the parent molecule.

Amide derivatives of 3-aminocaproate already been disclosed in this region. For example:

In the patent application of Japan No. 09087331 described amide p is osvitnye 3-aminocaproate, where amidalla side chain may contain from 2 to 30 carbon atoms. These compounds were presented in the form gelatinous oil agents.

In U.S. patent No. 6395282 describes immunogenic conjugates comprising a molecule-carrier connected with autoinduction gram-negative bacteria, where the specified autoinducer can be an amide derivative of 3-aminocaproate, and amidalla side chain can contain up to 34 carbon atoms. However, therapeutic application disclosed only forconjugatesand not forstand-aloneamide derivative.

In article Weiss et al. Research Communications in discrimination, Psychiatry and Behavior (1992), 17(3-4), 153 to 159) disclosed a series of amide derivatives of 3-aminocaproate and other 3-hexanamide-DL-ε-caprolactam and 3-dodecylamino-DL-ε-caprolactam. These compounds are represented as having only activity in vitro, but no significant effect in vivo.

In other words, although some alkylamine derivatives of 3-aminocaproate were definitely well-known in this field, for alkylamide derivatives of 3-aminocaproate wasn't described the actual pharmaceutical application.

The invention provides the use of compounds of General formula (I) or its pharmaceutically acceptable salt for a medicinal product for the treatment of inflammatory, Rastro the STV:

where

X represents a-CO-R1or-SO2-R2,

R1represents alkyl, allogeneically, alkoxy, halogenoalkane, alkanniny, alkynylaryl or alkylamino radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms), and

R2represents an alkyl radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms).

Alternative, R1and R2can be chosen independently of peptide radical containing from 1 to 4 peptidic fragments connected by peptide bonds (e.g., a peptide radical of 1-4 amino acid residues).

The carbon atom in position 3 caprolactamate ring is asymmetric, and therefore, the compounds in accordance with the present invention have two possible enantiomeric forms, i.e. “R” and “S” configuration. The present invention encompasses these two enantiomeric forms and all combinations of these forms, including racemic mixtures RS. The purpose of simplicity, when in structural formulas not until the Ana a certain configuration, it should be understood that presents both enantiomeric forms and mixtures thereof.

In the priority application GB 0327775.3 and 0417436.3 the same applicant is correct that the connection configuration “S” is preferred in these applications mistakenly illustrated by the General formula (I'), showing the configuration of “R”.

Preferably the compounds of General formula (I) or its pharmaceutically acceptable salts, which are used in accordance with this aspect of the invention, must be a compound of the formula (I')

where X has the same meaning as above.

The carbon atoms in R1and R2can be linear or branched.

Compounds of General formula (I) or (I') or their pharmaceutically acceptable salts can be such that the alkyl, halogenation, alkoxy, halogenoalkane, Alchemilla, Alchemilla or alkylamino part of the radical R1is either linear or branched, but contains a linear chain of at least 8 or at least 10 carbon atoms.

The invention also provides pharmaceutical compositions comprising as active ingredient a compound of General formula (I) or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient (filler) and/or carrier:

where

X represents a-CO-R1or-CO2-R2,

R1represents alkyl, allogeneically, alkoxy, halogenoalkane, alkanniny, alkynylaryl or alkylamino radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms), and

R2represents an alkyl radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms. 14 to 18 carbon atoms, of 13 to 17 carbon atoms).

Alternative, R1and R2can be chosen independently of peptide radical containing from 1 to 4 peptidic fragments connected by peptide bonds (e.g., a peptide radical of 1-4 amino acid residues).

Preferably the compound of General formula (I) or its pharmaceutically acceptable salt, used in accordance with this aspect of the invention, must be a compound of the formula (I')

where X has the same meaning as above.

Under a pharmaceutically acceptable salt refers, in particular, salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, Sul is phat, phosphate, diphosphate and nitrate or organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, almoat and stearate. Also within the scope of the present invention, when they can be used are salts formed from bases such as sodium hydroxide or potassium. For other examples of pharmaceutically acceptable salts can be referenced on the “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

The pharmaceutical composition may be presented in the form of solids, such as powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid Foundation may represent, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, destrin, starch, gelatin, cellulose, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidine and wax. Other appropriate pharmaceutically acceptable excipients and/or carriers known to specialists in this field.

Pharmaceutical compositions in accordance with the invention can also be presented in liquid form such as solutions, emulsions, suspensions or syrups. Appropriate liquid Foundation can represent, for example, organic solvents such as glycerol or glycols, and mixtures thereof in various proportions in water./p>

The invention also provides compounds and salts thereof of General formula (I)

where

X represents a-CO-R1or-SO2-R2,

R1represents alkyl, allogeneically, alkoxy, halogenoalkane, alkanniny, alkynylaryl or alkylamino radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms), and

R2represents an alkyl radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms).

Alternative, R1and R2can be chosen independently of peptide radical containing from 1 to 4 peptidic fragments connected by peptide bonds (e.g., a peptide radical of 1-4 amino acid residues).

Preferably the compound of General formula (I) or its pharmaceutically acceptable salt, used in accordance with this aspect of the invention, must be a compound of the formula (I')

where X has the same meaning as above.

Preferably the compounds of General formula (I) or (I') for use in the invention or their salts should be such to alkyl, halogenation, alkoxy, halogenoalkane, Alchemilla, Alchemilla or alkylamino part of the radical

R1was or linear or branched, but contain a linear chain of at least 8 to 10 carbon atoms.

In particular, preferred compounds of General formula (I) or (I') and their salts in accordance with any aspect of the present invention is selected from the group consisting of:

-(S)-3-hexadecanaminium;

-(S)-3-andeconomically;

-(S)-3-(undec-10-enoyl)aminocaproate;

-(S)-3-(undec-10-enoyl)aminocaproate;

-(S)-3-tetradecanoylphorbol;

-(R)-3-hexadecanaminium;

-(S)-3-octadecadienoate;

-(S)-(Z)-3-(hexadec-9-enoyl)aminocaproate;

-(S)-(Z)-3-(octadec-9-enoyl)aminocaproate;

-(R)-(Z)-3-(octadec-9-enoyl)aminocaproate;

-(S)-3-(2',2'-dimethylcarbamoyl)aminocaproate;

-(S)-3-(decyloxybenzoic)aminocaproate;

-(S)-(E)-3-(dodec-2-enoyl)aminocaproate;

-(S)-3-(Dec-9-ineliminably)aminocaproate;

-(S)-3-(decrimination)aminocaproate

and their salts.

The most preferred compounds must be selected from the group consisting of:

-(S)-3-hexadecanaminium (i.e. compounds of formula (I'), where R1represents hexadecanol), -(S)-3-(2',2'-DIMET dodecanoyl)aminocaproate, -(S)-3-(2',2'-dimethylpropyl)aminocaproate and their salts.

As noted above in the discussion of the prior art, certain alkylamine derivatives of 3-aminocaproate can be known as the connections themselves (although it is currently unknown whatanyone of them was described as such as pharmaceutical compositions or for medical use in anti-inflammatory context). In the prior art can be the description of linear alkylamine derivatives of 3-aminocaproate. Despite the fact that any connection is known as such, this connection is not intended to be a connection, declared itself in this invention, the applicants of the present invention waive any rights to it. Therefore, the applicant in the present description clearly distinguishes between linear alkyl derivatives are covered by the definition presented here of formulas (I) and (I'), and branched alkyl derivatives represented here by the formulas (I) and (I'). Used here the definition of R1in connection with these connections may include any alkyl derivatives; alternatively, R1may include all alkyl derivatives, except for certain specified linear alkyl derivatives; alternatively, R1may include all razvetvlennye the alkyl derivatives; and as another alternative, the definition of R1can exclude all alkylamine derivatives of 3-aminocaproate.

The invention includes certain compounds, compositions and their use, where the connection represented in hydrated or solvated form.

As stated in the Introduction, certain alkylaminocarbonyl connections themselves and composition/conjugates containing them, may already be known from the prior art. Any such known compounds or compositions must be excluded from the claims of the present invention by excluding specific or generalized class of compounds/compositions.

Described here amide derivatives of 3-aminocaproate represent functional BSCI. Their synthesis is relatively inexpensive when using the supplied here the easy way of synthesis; they are stable in human serum and, therefore, have excellent pharmacokinetic properties; they bioavailable when administered orally; they are highly active in vitro inhibitors of chemokines wide range with excellent selectivity, compared with non-chemokine-chemoattractant; they represent a highly active and effective anti-inflammatory agents in vivo models of inflammation in rodents; they is doing not associated with any significant toxicity at doses necessary to achieve the maximum therapeutic effect. These properties, taken together, indicate that amide derivatives of 3-aminocaproate are anti-inflammatory medicines have advantages over the previously described connections.

When compared with prior art, the improvement of the present invention is the introduction of a fragment of aminocaproate. However, the chemical structure of the side chain (or alkylamides, alkylsulfonamides or peptide) can also significantly influence the properties of the molecule, so that the alkyl substituents with a substitution in position 2 (relative amidocarbonyl) or position 1 (relative sulphamethazine group) greatly outweigh the connection with linear alkyl chains (or alkylamide, or alkylsulfonamides).

The peptides of the prior art (such as NR58-3.14.3) have disadvantages, namely that: (a) they are expensive and require solid-phase synthesis (at least for longer connections) and (b) they are very rapidly excreted through the kidneys, and (C) they are generally less active.

Aminoglutaramic prior art cheap, not excreted rapidly via the kidneys and more active, but they do not have metabolic stability.

Described here is an improvement, aminocaproate are cheap, not the kidneys and even more active, and are metabolically stable.

In accordance with this invention, an inflammatory disorder, intended for the prevention or treatment of compounds of General formula (I) or (I'), or their pharmaceutically acceptable salts, or pharmaceutical compositions or pharmaceutical agents containing them as active ingredients, include, in particular:

- autoimmune diseases such as multiple sclerosis;

cardiovascular disorders, including stroke, coronary artery lesions, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, such as the syndrome behceta, giant cell arthritis, rheumatic rheumatica, granulomatous's granulomatosis, vasculitis syndrome charge-Strauss, purple's disease-Solana and Kawasaki disease;

- a viral infection or replication, such as infections due to viruses or replication of viruses, including smallpox, herpes virus (e.g., Herpesvirus samiri), cytomegalovirus (CMB) or lentivirus;

- asthma;

- osteoporosis (low bone mineral density);

- growth of the tumor;

- rheumatoid arthritis;

- rejection of an organ transplant and/or delayed graft function or organ, for example, in patients with renal transplant;

p> - a disorder characterized by elevated levels of TNF-α;

- psoriasis;

skin wounds;

disorders caused by intracellular parasites such as malaria or tuberculosis;

- allergies; or

- Alzheimer's disease.

In accordance with this invention, other inflammatory disorders include:

- amyotrophic lateral sclerosis;

- fibrosis (in particular, pulmonary fibrosis, but not limited to fibrosis of the lung);

- formation (particularly in the abdomen and pelvic region);

- caused by antigen anamnestic reaction.

- suppression of the immune response.

These clinical indications fall under the General definition of inflammatory disorders or disorders characterized by elevated levels of TNF-α.

If there is a legal possibility invention also provides a method of treatment, mitigation or prevention of the symptoms of inflammatory diseases (including adverse inflammatory reaction to a substance) introduction to the patient an anti-inflammatory amount of a compound, composition or drug, as stated in this document.

The administration of a medicinal product in accordance with the invention can be local, oral, parenteral, intramuscular injection, etc.

Injected dose provided for l the drug funds in accordance with the invention, is from 0.1 mg to 10 g, depending on the type of active connections.

In accordance with the invention compounds of General formula (I) or (I') can be obtained using the following methods.

Obtaining compounds of General formula (I) or (I')

All compounds of General formula (I) or (I') can be easily obtained in accordance with the General methods known to the expert in this field.

However, following the preferred route of synthesis:

Chart 1

In accordance with the paths shown in figure 1:

- 3-aminocaproate is treated with acid chloride of the acid of General formula R1-CO-Cl, where R1represents alkyl, allogeneically, alkanniny or alkynylaryl radical, to obtain the compounds of General formula (I), where X represents a-CO-R1and R1represents alkyl, allogeneically, alkanniny or alkynylaryl radical; or

- 3-aminocaproate treated with isocyanate of General formula R'-NCO, where R' represents alkyl, to obtain the compounds of General formula (I), where X represents a-CO-R1and R1represents alkylamino radical;

- 3-aminocaproate treated with sulfochloride General formula R2-SO2Cl, where R2represents alkyl, receive compounds of General formula (I), where X represents-SO2-R2and R2represents an alkyl radical; or

- 3-aminocaproate treated with chloroformiate General formula R'-O-CO-Cl, where R'represents alkyl, to obtain the compounds of General formula (I), where X represents a-CO-R1and R1represents an alkoxy radical.

The reaction, shown in figure 1, can be performed, for example, chloroform or dichloromethane. The most preferred reaction solvent is dichloromethane. The above reaction is preferably carried out in the presence of a base, for example Na2CO3.

All of the above reactions can be carried out at ambient temperature (approximately 25°C) or in General at a temperature of from 20 to 50°C.

Definition

The term "about" refers to the interval about the considered values. Used in this patent application the term "approximately X" means the interval from X minus 10% of X to X plus 10% of X, and preferably the interval from X minus 5% of X to X plus 5% of X.

Use the numeric range in the present description is intended to explicitly include within the scope of the invention all the individual integers within range and all combinations of the values of the upper and lower limit within the broad scope given to the CSOs range. Therefore, for example, range from 4 to 20 carbon atoms, defined in relation to (among others) of the formula I, is intended to include all integers from 4 to 20 and all Abdumanonov each combination of the upper and lower values, illustrated definitely or indefinitely.

Used herein, the term "including" should be read as meaning and "comprising"and "consisting of". Therefore, when the invention relates to pharmaceutical compositions comprising as active ingredient the compound, this terminology is intended to encompass compositions, which can be other active ingredients, and also compositions that include only one specific active ingredient.

Used herein, the term "peptide fragment" is intended to include the following 20 natural proteogenic amino acid residues:

DESIGNATIONVALUE
AlaAlanine
ysCysteine
AspAspartic acid
GluGlutamic acid
PhePhenylalanine
GlyGlycine
HisHistidine
IleIsoleucine
LysLysine
LeuLeucine
MetMethionine
AsnAsparagine
ProProline
GlnGlutamine
ArgArginine
SerSerine
ThrThreonine
ValValine
TrpTryptophan
TyrTyrosine

Modified and unusual amino acid residues and peptido-mimetics also intended to encompass the term "peptide fragments".

In the absence of other definitions of all technical and scientific t is rmini, used herein have the same meaning as is commonly understood by the average expert in the field that applies the present invention. Similarly, all publications, patent applications, all patents and other references mentioned herein are incorporated as references (when permitted by law).

The following examples are presented to illustrate the above procedures and in no way should be considered as limiting the scope of invention.

Drawings

Figure 1 provides a comparison of (R)- and (S)-enantiomers amide derivative aminocaproate as inhibitors of migration induced MCP-1.

Examples

General procedure for the synthesis of the parent compounds

Hydrochloride (R)- and (S)-3-aminocaproate and hydropyridine-5-carboxylates (R,R)- and (S,S)-3-aminocaproate synthesized according to literature data (cf. Boyle et al., J. Org. Chem., (1979), 44, 4841-4847; Divided et al., J. Med. Chem. (1997), 40, 3508-3515).

Example 1: (S)-3-hexadecyloxypropyl:

Hydrochloride (S)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (25 ml) are added to a solution of hexadecasaccharide (5 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase is additionally extracted dichlor the tan (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the connection header (1,41 g; 77%).

Melting point: 99-100°C.

(c = 1, CHCl3) = +32,0.

IR: νmax(cm-1): 3325, 3272 (NH), 1666, 1655, 1631 (CO), 1524 (NH).

1H NMR (δH, 500 MHz, CDCl3): to 6.88 (1H, d, J AND 5.5, CHNH), 6,72 (1H, Shir. with a, CH2NH), of 4.49 (1H, DDD, J 11, 6, 1, CHNH), 3,29-and 3.16 (2H, m, CH2NH), 2,17 (2H, t, J 7.5 to, CH2CONH), 2,03 (1H, Shir. d, J 13,5, ring CH), 1,98-1,89 (1H, m, ring CH), 1.85 to at 1.73 (2H, m, ring CH), 1,58 (2H, Shir. kN J 7,0, CH2CH2CONH), USD 1.43 (1H, Shir. KD, J 14, 3, ring CH), 1,38-of 1.29 (1H, Shir. m, ring CH), 1,29-1,14 (24H, m, (CH2)12and of 0.83 (3H, t, J 6,5, CH3).

13C NMR (δC, 125 MHz, CDCl3): 175,9, 172,3 (CO), 52,0 (NHCHCO), 42,1 (NCH2), 36,6, 31,9, 31,7, 29,6 (×6), 29,4, 29,3 (×2), 29,2, 28,8, 27,9, 25,6, 22,6 (CH2) and 14.1 (CH3).

m/z (C22H42N2O2Na): 389,31450 (calculated: 389,3144).

Example 2: (S)-3-underageerotica:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) are added to a solution of undecanoate (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). United organicheskoi dried over Na 2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (397 mg; 67%).

Melting point: 91-92°C.

(c = 1, CHCl3) = +30,2.

IR: nmax(cm-1): 3342, 3313 (NH), 1676, 1638 (CO), 1519 (NH); 3342, 3292 (NH), 1671, 1639 (CO), 1513 (NH).

1H NMR (dH, 500 MHz, d6-DMSO): 7,76 (1H, t,J6, CH2NH), to 7.68 (1H, d,J7, CHNH), to 4.38 (1H, DD,J10, 7, CHNH)and 3.15 (1H, DDD,J15,5, 11, 5, CHHNH), totaling 3.04 (1H, dt,J13, 6, CHHNH), 2,19-to 2.06 (2H, m, CH2CONH), of 1.85 (1H, dt,J10,5, 3, C-5 H), 1.77 in by 1.68 (2H, m, C-4 H, C-6 H), 1,60 (1H, CT,J12, 3,5, C-5 H)of 1.46 (2H, Shir. kNJ6,5, CH2CH2CONH), of 1.35 (1H, CD,J12,5, 3, C-4 H), 1,31-1,13 (15H, m, (CH2)7+ C-6 H) and of 0.85 (3H, t,J7,0, CH3).

13C NMR (dC, 125 MHz, d6-DMSO): of 174.4 (CO-ring), is 171.3 (CO-chain), 51,3 (NHCHCO), 40,7 (NCH2), 35,2, 31,4, 31,3, 29,1, 29,0 (×2), 28,9, 28,8, 28,7, 27,8, 25,4, 22,2

(CH2) and 14.0 (CH3).

m/z (C17H32N2O2Na): 319,23540 (calculated: 319,2361).

Example 3: (S)-3-(undec-10-enoyl)aminocaproate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of undec-10-tailhold (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional the additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (423 mg; 72%).

Melting point: 83-84°C.

(c = 1, CHCl3) = +40,1.

IR: nmax(cm-1): 3327, 3273 (NH), 1655, 1630 (CO), 1521 (NH).

1H NMR (dH, 500 MHz, d6-DMSO): of 7.75 (1H, t,J6, CH2NH), 7,66 (1H, d,J7, CHNH), USD 5.76 (1H, DDT,J17, 10, 6,5 CH2=CH), 4,96 (1H, DK,J17, 2, CHH=CH), 4,96 (1H, DDT,J17, 2, 1, CHH=CH), 4,36 (1H, DD,J10, 7, CHNH), 3,14 (1H, DDD,J15,5, 11,5, 5, CHHNH), 3,03 (1H, shirt,J13, 5,5, CHHNH), 2,16-to 2.06 (2H, m, CH2CONH), to 1.98 (2H, shirk,J7, CH2=CHCH2), of 1.85 (1H, dt,J10,5, 3, C-5 H), a 1.75-to 1.67 (2H, m, C-4 H, C-6 H), 1,60 (1H, CT,J13, 3,5, C-5 H), the 1.44 (2H, Shir. kNJ7, CH2CH2CONH), 1,39-of 1.27 (3H, m, CH2=CHCH2CH2+ C-4 H) and 1.31-of 1.13 (9H, m, (CH2)4+ C-6 H).

13C NMR (dC, 125 MHz, d6-DMSO): 174.4 (CO-ring), is 171.3 (CO-chain), 138,9 (CH2=CH), to 114.7 (CH2=CH), 51,3 (NHCHCO), 40,7 (NCH2), 35,3, 33,3, 31,3, 29,0, 28,9 (×2) 28,7, 28,6, 28,4, 27,8 and 25.4 (CH2).

m/z (C17H30N2O2Na): 317,21970 (calculated: 317,2205).

Example 4: (S)-3-(undec-10-enoyl)aminocaproate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of undec-10-enoyl lorida (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours The organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (362 mg; 62%).

Melting point: 73-75°C.

(c = 1, CHCl3) = +42,1.

IR: nmax(cm-1): 3332, 3295 (NH), 1667, 1633 (CO), 1523 (NH).

1H NMR (dH, 500 MHz, d6-DMSO): 7,76 (1H, t,J5,5, CH2NH), to 7.68 (1H, d,J7, CHNH), 4,36 (1H, DD,J11, 7, CHNH), and 3.16 (1H, DDD,J15,5, 11,5, 5, CHHNH), 3,03 (1H, shirt,J14, 7, CHHNH), 2,17-2,07 (4H, m, CH2CONH + CH2CCH), of 1.85 (1H, m, C-5 H), 1.77 in-1,67 (2H, m, C-4 H, C-6 H)of 1.62 (1H, shirt,J13, 3,0, C-5 H), 1,50 of 1.28 (5H, m, CH2CH2CONH +

HCCCH2CH2+ C-4 H) and 1.28-of 1.13 (9H, m, (CH2)4+ C-6 H).

13C NMR (dC, 125 MHz, d6-DMSO): of 174.4 (CO-ring), is 171.3 (CO-chain), and 84.6 (CH2CCH), 71,1 (CH2CCH)51,3 (NHCHCO), 40,7 (NCH2), 35,2, 31,3, 29,0, 28,8, 28,7, 28,5, 28,2, 28,0, 27,8, 25,4 and 17.8 (CH2).

m/z (C17H28N2O2Na): 317,20470 (calculated: 315,2048).

Example 5: (S)-3-dodecadodecahedron:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) are added to a solution of dodecanolide (2 mmol) in dichloromethane (25 ml) at the temperature of environment is the environment and the reaction mixture is stirred for 2 hours The organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (439 mg; 71%).

Melting point: 93-94°C.

(c = 1, CHCl3) = +35,5.

IR: nmax(cm-1): 3324, 3267 (NH), 1666, 1630 (CO), 1521 (NH).

1H NMR (dH, 500 MHz, d6-DMSO): 7,76 (1H, Sirs, CH2NH), to 7.67 (1H, d,J7, CHNH), to 4.38 (1H, DD,J10,5, 7,5, CHNH)and 3.15 (1H, DDD,J15,5, 11,5, 5, CHHNH), 3,05 (1H, dt,J14,5, 5,5, CHHNH), 2,17-2,07 (2H, m, CH2CONH), 1,90 and 1.80 (1H, m, C-5 H), 1.77 in by 1.68 (2H, m, C-4 H, C-6 H)of 1.62 (1H, shirt,J12, 3,5, C-5 H)of 1.46 (2H, SirkinJ6,0, CH2CH2CONH), 1,36 (1H, CD,J12,5, 2,5, C-4 H), 1,31-1,13 (17H, m, (CH2)8+ C-6 H) and of 0.85 (3H, t,J6,5, CH3).

13C NMR (dC, 125 MHz, d6-DMSO): of 174.4 (CO-ring), 171,2 (CO-chain), 51,3 (NHCHCO), 40,7 (NCH2), 35,3, 31,4, 31,3, 29,1 (×3), 29,0 (×2), 28,8, 28,7, 27,8, 25,4, 22,2

(CH2) and 14.0 (CH3).

m/z (C18H34N2O2Na): 333,25150 (calculated: 333,2518).

Example 6: (S)-3-tetradecanoylphorbol:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) are added to a solution of tetradecanoylphorbol (2 mmol) in dichloromethane (25 ml) at ambient temperature cf the water and the reaction mixture is stirred for 2 hours The organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (412 mg; 61%).

Melting point: 97-98°C.

(c = 1, CHCl3) = +33,2.

IR: nmax(cm-1): 3326, 3273 (NH), 1666, 1655, 1631 (CO), 1523 (NH).

1H NMR (dH, 500 MHz, CDCl3): 6,87 (1H, d,J5,5, CHNH), 6,66-6,48 (1H, SIRM, CH2NH), 4,50 (1H, DD,J11, 6, CHNH), 3,30-and 3.16 (2H, m, CH2NH), to 2.18 (2H, t,J7,5, CH2CONH), 2,04 (1H, shirt,J13,5, ring CH), 2,00-of 1.92 (1H, m, ring CH), 1,86-of 1.74 (2H, m, ring CH), 1,59 (2H, SirkinJ7,0, CH2CH2CONH), USD 1.43 (1H, shirk,J12,5, ring CH), 1,31 (1H, shirk,J13, ring CH), 1,31-1,13 (20H, m, (CH2)10and of 0.85 (3H, t,J6,5, CH3).

13C NMR (dC, 125 MHz, CDCl3): 175,9, 172,3 (CO), 52,0 (NHCHCO), 42,1 (NCH2), 36,6, 31,9, 31,7, 29,6 (×4), 29,4, 29,3 (×2), 29,2, 28,8, 27,9, 25,6, 22,6 (CH2) and 14.1 (CH3).

m/z (C20H38N2O2Na): 361,28270 (calculated: 361,2831).

Example 7: (R)-3-hexadecyloxypropyl:

Hydropyridine-5-carboxylate (R,R)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (25 ml) are added to a solution of hexadecasaccharide (5 mmol) in dichloromethane (25 ml) at a temperature of about the action and the reaction mixture is stirred for 2 hours The organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (1.23 g; 67%).

Melting point: 99-100°C.

(c = 1, CHCl3) = -32,0.

Example 8: (S)-3-octadecadienoate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) are added to a solution of octadecanethiol (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain specified in the title compound (648 mg; 82%).

Melting point: 87-88°C.

(c = 1, CHCl3) = +31,9.

IR: nmax(cm-1): 3327, 3272 (NH), 1667, 1655, 1631 (CO), 1524 (NH).

1H NMR (dH, 500 MHz, CDCl3): to 6.88 (1H, d,J5,5, CHNH), 6,72 return of 6.58 (1H, SIRM, CH2NH), 4,50 (1H, DD,J11, 6, CHNH), 3,29-and 3.16 (2H, m, CH2NH), 2,17 (2H, t,J7,5, CH2CONH), 2,03 (1H, shirt,J13, ring CH), 1,99-1,90 (1H, m, ring CH) 1,86-of 1.73 (2H, m, ring CH), 1,58 (2H, SirkinJ7,0, CH2CH2CONH), of 1.42 (1H, shirk,J14, 3, ring CH), 1,38-of 1.30 (1H, charm, ring CH), 1,30-1,14 (28H, m, (CH2)14) and 0.84 (3H, t,J6,5, CH3).

13C NMR (dC, 125 MHz, CDCl3): 175,9, 172,3 (CO), 52,0 (NHCHCO), 42,1 (NCH2), 36,6, 31,9, 31,7, 29,6 (×8), 29,4, 29,3 (×2), 29,2, 28,8, 27,9, 25,6, 22,6 (CH2) and 14.1 (CH3).

m/z (C24H46N2O2Na): 417,34460 (calculated: 417,3457).

Example 9: (S)-(Z)-3-(hexadec-9-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of (Z)-hexadec-9-tailhold (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (406 mg; 56%).

Melting point: 67-68°C.

(c = 1, CHCl3) = +33,2.

IR: nmax(cm-1): 3324, 3268 (NH), 1655, 1630 (CO), 1524 (NH).

1H NMR (dH, 500 MHz, CDCl3): to 6.88 (1H, d,J5,5, CHNH), to 6.67 (1H, Sirs, CH2NH), 5,33-a 5.25 (2H, m, CH=CH), 4,50 (1H, DDD,J11, 6, 1, C<> HNH), 3,29-and 3.16 (2H, m, CH2NH), 2,17 (2H, t,J7,5, CH2CONH), 2,03 (1H, shirt,J13, ring CH), 1,99-1,90 (5H, m, ring CH + CH2CH=CHCH2), 1,84-1,72 (2H, m, ring CH), 1,58 (2H, SirkinJ7,0, CH2CH2CONH), USD 1.43 (1H, shirk,J14, 3, ring CH), 1,38-of 1.30 (1H, charm, ring CH), 1,30-1,14 (16H, m, (CH2)4CH2CH=CHCH2(CH2)4) and 0.84 (3H, t,J7, CH3).

13C NMR (dC, 125 MHz, CDCl3): 175,9, 172,3 (CO), 129,8 (×2) (CH=CH), 52,0 (NHCHCO), 42,0 (NCH2), 36,6, 31,7 (×2), 29,7 (×2), 29,2 (×2), 29,1, 29,0, 28,8, 27,9, 27,2, 27,1, 25,6, 22,6 (CH2) and 14.1 (CH3).

m/z (C22H40N2O2Na): 387,29700 (calculated: 387,2987).

Example 10: (S)-(Z)-3-(octadec-9-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of (Z)-octadec-9-tailhold (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (514 mg; 66%).

Melting point: 66-67°C.

(c= 1, CHCl3) = +30,9.

IR: nmax(cm-1): 3327, 3268 (NH), 1655, 1631 (CO), 1523 (NH).

1H NMR (dH, 500 MHz, CDCl3): to 6.88 (1H, d,J5,5, CHNH), 6,74 (1H, shirt,J5, CH2NH), 5,33-5,24 (2H, m, CH=CH), of 4.49 (1H, DDD,J11, 6, 1,5, CHNH), 3,29-3,14 (2H, m, CH2NH), of 2.16 (2H, t,J7,5, CH2CONH), 2,03 (1H, shirt,J13,5, ring CH), 1,99-1,89 (5H, m, ring CH + CH2CH=CHCH2), 1,84-1,72 (2H, m, ring CH), 1,58 (2H, SirkinJ7,0, CH2CH2CONH), of 1.42 (1H, shirk,J14, 3, ring CH), 1,38-of 1.30 (1H, charm, ring CH), 1,30-1,14 (20H, m, (CH2)6CH2CH=CHCH2(CH2)4and of 0.83 (3H, t,J7, CH3).

13C NMR (dC, 125 MHz, CDCl3): 175,9, 172,3 (CO), 129, 9mm, 129,7 (CH=CH), 52,0 (NHCHCO), 42,0 (NCH2), 36,6, 31,8, 31,7, 29,7 (×2), 29,5, 29,3 (×3), 29,2, 29,1, 28,8, 27,9, 27,2, 27,1, 25,6, 22,6 (CH2) and 14.1 (CH3).

m/z (C24H44N2O2Na): 415,32820 (calculated: 415,3300).

Example 11: (R)-(Z)-3-(octadec-9-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (R,R)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of (Z)-octadec-9-tailhold (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2COsub> 3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (574 mg; 73%).

Melting point: 66-67°C.

(c = 1, CHCl3) = -31,4.

Example 12: (S)-3-(2',2'-dimethylcarbamoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of 2,2-dimethyldodecylamine (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (543 mg; 80%).

Melting point: 41-42°C.

(c = 1, CHCl3) = +28,0.

IR: nmax(cm-1): 3403, 3265 (NH), 1673, 1641 (CO), 1497 (NH).

1H NMR (dH, 500 MHz, CDCl3): was 7.08 (1H, d,J5,5, CHNH), to 6.67 (1H, Sirs, CH2NH), of 4.44 (1H, DD,J11, 5,5, CHNH), 3,28 is 3.15 (2H, m, CH2NH), a 2.01 (1H, shirt,J13, ring CH), 1,98-1,89 (1H, m, ring CH), 1,84-1,72 (2H, m, ring CH), 1,47-of 1.30 (3H, charm, ring CH + CH2CME2CONH), 1,27-1,15 (17H, IRM, ring CH +(CH2)8) of 1.13 (3H, s, SEEeIU)of 1.12 (3H, s, CMEIU) and 0.82 (3H, t,J7, CH2CH3).

13C NMR (dC, 125 MHz, CDCl3): 177,1, 176,0 (CO), 52,0 (NHCHCO), 41,9 (SEEe2), 42,1, 41,3, 31,8, 31,5, 30,1, 29,6, 29,5 (×2), 29,3, 28,9, 27,9 (CH2), 25,3, 25,2 (CH3), 24,8, 22,6 (CH2) and 14.1 (CH3).

m/z (C20H38N2O2Na): 361,28350 (calculated: 361,2831).

Compound 12 was later subjected to recrystallization in a larger scale, and this batch of material had the following properties: the melting point of 51-52°C.(c = 1, CHCl3) +28,0;(c = 0,87, Meon) +13,3.

Example 13: (S)-3-(decyloxybenzoic)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) are added to a solution of decipherment (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (469 mg; 74%).

Melting point: 40-41°C.

(c = 1, CHCl3) = +31,4.

Is to: n max(cm-1): 3352, 3300 (NH), 1682, 1657, 1637 (CO), 1513 (NH).

1H NMR (dH, 500 MHz, CDCl3): 6,86 (1H, Sirs, CH2NH), 6,72 (1H, d,J6 CHNH), of 4.49 (1H, DD,J11, 6, CHNH), 3,99 (2H, t,J6, OCH2), 3,26-3,14 (2H, m, CH2NH), 2,04 (1H, shirt,J13,5, ring CH), 2,00 is 1.91 (1H, m, ring CH), 1,82 by 1.68 (2H, m, ring CH), of 1.55 (2H, SirkinJ7,0, CH2CH2O)to 1.48 (1H, shirk,J14, 2,5, ring CH), 1,38 to 1.31 (1H, charm, ring CH), 1,29-1,17 (14H, m, (CH2)7and of 0.83 (3H, t,J7, CH3).

13C NMR (dC, 125 MHz, CDCl3): 175,8, 155,9 (CO), 65,0 (OCH2), 53,5 (NHCHCO), 42,0 (NCH2), 32,1, 31,8, 29,5 (×2), 29,2 (×2), 29,0, 28,8, 28,0, 25,8, 22,6 (CH2) and 14.1 (CH3).

m/z (C17H32N2O3Na): 335,23190 (calculated: 335,2311).

Example 14: (S)-(E)-3-(dodec-2-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of dodec-2-tailhold (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (472 mg; 77%)./p>

Melting point: 87-88°C.

(c = 1, CHCl3) = +44,7.

IR: nmax(cm-1): 3382, 3331 (NH), 1660, 1616 (CO), 1520 (NH).

1H NMR (dH, 500 MHz, CDCl3): 6,94 (1H, d,J5,5, CHNH), at 6.84 (1H, Sirs, CH2NH), is 6.78 (1H, dt,J15,5, 7, CH2CH=CH), 5,80 (1H, d,J15,5, CH2CH=CH), 4,56 (1H, DDD,J11, 6, 1,5, CHNH), 3,29 is 3.15 (2H, m, CH2NH), 2,11 (2H, K,J7, CH2CH=CH), 2,07 (1H, shirt,J13,5, ring CH), 1,98-1,90 (1H, m, ring CH), 1,86-of 1.73 (2H, m, ring CH), the 1.44 (1H, shirk,J14, 2,5, ring CH), 1.41 to of 1.29 (3H, charm, ring CH + CH2CH2CH=CH), 1,29-to 1.14 (12H, m, (CH2)6) and 0.82 (3H, t,J6,5, CH3).

13C NMR (dC, 125 MHz, CDCl3): 175,9, 165,0 (CO), 144,8, to 123.5 (CH=CH), 52,0 (NHCHCO), 42,0 (NCH2), 32,0, 31,8, 31,6, 29,4 (×2), 29,2, 29,1, 28,8, 28,2, 27,9, 22,6 (CH2) and 14.1 (CH3).

m/z (C18H32N2O2Na): 331,23570 (calculated: 331,2361).

Example 15: (S)-3-(Dec-9-ineliminably)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of Dec-9-fenilizotsianata (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and arevut in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (347 mg; 56%).

Melting point: 98-99°C.

(c = 1, CHCl3) = +27,3.

IR: nmax(cm-1): 3365, 3327, 3276 (NH), 1619, (CO), 1551 (NH).

1H NMR (dH, 500 MHz, CDCl3): only 6.64 (1H, Sirs, ring CH2NH), 6,12 (1H, d,J6 CHNH), of 5.75 (1H, DDD,J17, 10, 6,5, 1,5, CH2=CH), to 5.21-5,12 (1H, SIRM, urea CH2NH), is 4.93 (1H, DK,J17, 1,5, CHH=CH), to 4.87 (1H, shirt,J10, CHH=CH), 4,49 (1H, DD,J11, 6, NHCHCO)at 3.25 (1H, DDD,J15,5, 12, 4, ring CH2N), 3,17 (1H, dt,J14, 6, ring CH2N), 3,11-to 3.02 (2H, m urea NHCH2), 2,05-to 1.87 (4H, charm, ring CH ×2 + CH2CH=CH), 1,82 is 1.70 (2H, m, ring CH), 1,48-of 1.36 (3H, SIRM, the chain CH2CH2NH, + ring CH), 1,36-of 1.27 (3H, m, ring CH + chain CH2and 1,27-1,17 (8H, m, chain (CH2)4).

13C NMR (dC, 125 MHz, CDCl3): 177,2, 157,6 (CO), 139,1, 114,1 (CH=CH), 52,7 (NHCHCO), 42,1, 40,3 (NCH2), 33,7, 32,9, 30,3, 29,4, 29,3, 29,0, 28,8 (×2), 27,9 and 26,9 (CH2).

m/z (C17H31N3O2Na): 332,23150 (calculated: 332,2314).

Example 16: (S)-3-(decrimination)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) are added to a solution decylsulfate (2 mmol) in dichloromethane (25 ml) at a temperature surrounding the it environment and the reaction mixture is stirred for 2 hours The organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (eluent: EtOAc to 9:1 EtOAc:MeOH) to obtain specified in the title compound (401 mg; 64%).

Melting point: 97-98°C.

(c = 1, CHCl3) = +27,7.

IR: nmax(cm-1): 3359, 3316 (NH), 1621, (CO), 1558 (NH).

1H NMR (dH, 500 MHz, CDCl3): 6,62 (1H, Sirs, ring CH2NH), 6,09 (1H, d,J6 CHNH), 5,16 (1H, shirt,J5, urea CH2NH), 4,48 (1H, DDD,J11, 6, 1, NHCHCO), 3,26 (1H, DDD,J16, 11, 5, ring CH2N), 3,17 (1H, dt,J15, 7, ring CH2N), 3,11-to 3.02 (2H, m urea NHCH2), 2,02 (1H, sirdJ14, ring CH), 1,96-to 1.87 (1H, m, ring CH), 1,83 is 1.70 (2H, m, ring CH), 1,48-of 1.27 (4H, charm, ring CH ×2 + chain CH2), 1,27-1,14 (14H, m, (CH2)7) and 0.82 (3H, t,J7, CH3).

13C NMR (dC, 125 MHz, CDCl3): 177,2, 157,6 (CO), and 52.7 (NHCHCO), 42,1, 40,4 (NCH2), 32,9, 31,8, 30,2, 29,6, 29,5, 29,4, 29,3, 28,8, 27,9, 26,9, 22,6 (CH2) and 14.1.

m/z (C17H33N3O2Na): 334,24880 (calculated: 334,2470).

Example 17: (R)-3-(2',2'-dimethylcarbamoyl)aminocaproate:

Hydropyridine-5-carboxylate (R,R)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of 2,2-Dimethylol is coolglide (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours The organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (EtOAc:hexane 1:3 to EtOAc) to obtain (R)-3-(2',2'-dimethylcarbamoyl)aminocaproate (515 mg; 76%); melting point: 48-49°C;(c = 1, CHCl3) -25,7;(c = 0.5, Meon) -12,2.

Compound 17 was later subjected to recrystallization in a larger scale, and this batch of material had the following properties: melting point 50-51°C.

Example 18: (S)-3-(2',2'-dimethylpentane)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (20 mmol) and Na2CO3(60 mmol) in water (50 ml) was added to a solution of 2,2-dimethylethanolamine (20 mmol) in dichloromethane (50 ml) at ambient temperature and the reaction mixture is stirred for 12 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is recrystallized from EtOAc/hexane to obtain (S)-3-(2',2'-dimethylpentane)aminocaproate (3.50 g; 77%); melting point: 84-85°C;(c = 1, CHCl3) +30,7; nmax/cm-13387, 3239 (NH), 1655, 134 (CO), 1507 (NH);

dH(500 MHz, CDCl3) was 7.08 (1H, d,J5, CHNH), 6,53 (1H, Sirs, CH2NH), of 4.45 (1H, DDD,J11, 5,5, 1,5, CHNH), 3,29-and 3.16 (2H, m, CH2NH), 2,00 (1H, shirt,J13, ring CH), 1,98-of 1.92 (1H, m, ring CH), 1,84-of 1.73 (2H, m, ring CH), 1,47-of 1.30 (4H, charm, ring CH ×2 + CH2CME2CONH), 1,23-of 1.15 (2H, m, CH2CH3) to 1.14 (3H, s, SEEeIU)of 1.13 (3H, s, CMEIU) and 0.84 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 177,0, 176,1 (CO), 52,1 (NHCHCO), 43,6, 42,0 (×2, one of which is aSEEe2), 31,5, 28,9 of 27.9 (CH2), 25,3, 25,2 (CH3)and 18.0 (CH2) and 14.5 (CH3); m/z (M+C13H24N2O2requires 240,18378) 240,18437.

Example 19: (S)-3-(2',2'-dimethylpent-4-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (20 mmol) and Na2CO3(60 mmol) in water (50 ml) was added to a solution of 2,2-dimethylpent-4-tailhold (20 mmol) in dichloromethane (50 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (1:1 EtOAc:hexane to EtOAc) to obtain (S)-3-(2',2'-dimethylpent-4-enoyl)aminocaproate (1,43g; 32%); melting point: 71-72°C; (c = 1, CHCl3) +27,7; nmax/cm-13395, 3304 (NH), 1675, 1633 (CO), 1534 (NH); dH(500 MHz, CDCl3) 7,10 (1H, d,J4,5, CHNH), 6,48 (1H, Sirs, CH2NH), of 5.68 (1H, DDT,J17, 10, 7,5, CH=CH2), 5,02 (1H, shirt,J17 CH=CHH)to 5.00 (1H, shirt,J10, CH=CHH), of 4.45 (1H, DD,J11, 5,5, CHNH), 3,30-3,17 (2H, m, CH2NH), and 2.27 (1H,J14, 7,5, CHHCH=CH2), 2,22 (1H, DD,J14 and 7.5, CHHCH=CH2), a 2.01 (1H, shirt,J13, ring CH), 1,98-of 1.92 (1H, m, ring CH), 1.85 to at 1.73 (2H, m, ring CH), 1,47-of 1.30 (2H, charm, ring CH ×2), of 1.16 (3H, s, SEEeIU), and 1.15 (3H, s, CMEIU); dC(125 MHz, CDCl3) 176,4, 175,9 (CO), 134,2 (CH=CH2), 117,8 (CH=CH2), 52,1 (NHCHCO), 45,2, 42,1 (CH2), 41,9 (SEEe2), 31,5, 28,9 of 27.9 (CH2), and 25,0 24,9 (CH3); m/z (M+C13H22N2O2requires 238,16813) 238,16834.

Example 20: (S)-3-(2',2'-dimethylpropyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (15 ml) was added to a solution of 2,2-dimethylpropanamide (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture is stirred for 12 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is recrystallized from EtOAc/hexane to obtain (S)-3-(2'2'-dimethylpropionic)aminocaproate (645 mg; 61%); melting point: 126-127°C;(c = 1, CHCl3) +39,5; nmax/cm-13381, 3255 (NH), 1680, 1632 (CO), 1506 (NH); dH(500 MHz, CDCl3) 7,10 (1H, d,J5,0, CHNH), to 6.75 (1H, Sirs, CH2NH), was 4.42 (1H, DDD,J11, 5,5, 1,5, CHNH), 3.27 to and 3.16 (2H, m, CH2NH), 2,03-1,89 (2H, m, 2 × ring CH), 1,83-1,71 (2H, m, 2 × ring CH), 1,45 of 1.28 (2H, m, 2 × ring CH), and 1.15 (9H, s, 3 × CH3); dC(125 MHz, CDCl3) 177,7, 176,1 (CO), 52,1 (NHCHCO), 42,0 (CH2N)40,5 (CCO), 31,5, 28,9 of 27.9 (CH2lactam), 27,4 (3 × CH3).

m/z (MPa+C11H20N2O2Na requires 235,141699) 235,142237; (MN+C11H21N2O2requires 213,1597543) 213,160246.

Example 21: (S)-3-(2',2'-dimethylbutyryl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (15 ml) was added to a solution of 2,2-dimethylbutyramide (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture is stirred for 12 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is recrystallized from EtOAc/hexane to obtain (S)-3-(2',2'-dimethylbutyryl)aminocaproate (562 mg, 50%); melting point: 106-107°C;(c = 1, CHCl3) +33,6; nmax/cm-1 3400, 3278 (NH), 1677, 1630 (CO), 1500 (NH); dH(500 MHz, CDCl3) was 7.08 (1H, d,J5,0, CHNH), 6,72 (1H, Sirs, CH2NH), of 4.44 (1H, DDD,J11, 5,5, 1,5, CHNH), 3,28-and 3.16 (2H, m, CH2NH), 2,04-1,90 (2H, m, 2 × ring CH), 1,83-1,72 (2H, m, 2 × ring CH), 1,57-of 1.44 (2H, m, CH2CH3), 1,44-of 1.30 (2H, m, 2 × ring CH) of 1.12 (3H, s, CH3) a 1.11 (3H, s, CH3) and 0.78 (3H, t,J7,5, CH2CH3); dC(125 MHz, CDCl3) 177,0, 176,0 (CO), 52,1 (NHCHCO), 42,2 (CCO), 42,0 (CH2N)33,7 (CH2CH3), 31,6, 28,9 of 27.9 (CH2lactam), 24,8, 24,7 (CCH3) and 9.1 (CH2CH3); m/z (MN+C12H23N2O2requires 227,1760) 227,1767.

Example 22: (S,E)-3-(2',2'-dimethylmaleic-4'-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (10 mmol) and Na2CO3(30 mmol) in water (30 ml) was added to a solution of 2,2-dimethylmaleic-2-tailhold (untreated, in the above reaction) (10 mmol) in dichloromethane (30 ml) at ambient temperature and the reaction mixture is stirred for 12 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (1:1 EtOAc:hexane to EtOAc) to obtain (S,E)-3-(2',2'-dimethylmaleic-4'-enoyl)aminocaproate (2,12g; 63%); (c = 1, CHCl3) +21,6; nmax/cm-13264 (NH), 1639 (CO), 1497 (NH); dH(500 MHz, CDCl3) to 7.09 (1H, d,J5,5, CHNH), 6,67-6,32 (1H, SIRM, CH2NH), 5,42 (1H, dt,J15, 6,5, CH=CH), 5,28 (1H, dt,J15, 7, CH=CH), of 4.44 (1H, DD,J11, 5,5, CHNH), 3,30-3,17 (2H, m, CH2NH), of 2.20 (1H, DD, 13,5, 7, CH=CHCH2), and 2.14 (1H, DD, 13,5, 7, CH=CHCH2), 2,01-to 1.87 (4H, charm, ring CH ×2, + CH2CH=CH), 1,87-of 1.74 (2H, m, ring CH), 1,47-1,32 (2H, m, ring CH), 1,27-1,15 (10H, SIRM, (CH2)5) of 1.13 (3H, s, SEEeIU)of 1.12 (3H, s, CMEIUand of 0.83 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 176,8, 176,0 (CO), 134,2, 125,2 (CH=CH), 52,1 (NHCHCO)and 43.9 (CH2), 42,1 (×2) (CH2+SEEe2), 32,6, 31,8, 31,5, 30,1, 29,4, 29,1 (×2), 28,9, 27,9 (CH2), 25,0, 24,8 (CH3) and 22.6 (CH3); m/z (MN+C20H37N2O2requires 337,2855) 337,2858.

Example 23: (S)-3-(2',2',5'-trimethylene-4'-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (4.11 g, 16 mmol) and

Na2CO3(5,09 g, 48 mmol) in water (50 ml) was added to a solution of 2,2,5-trimethylene-4-tailhold (16 mmol) in dichloromethane (50 ml) at ambient temperature and the reaction mixture is stirred for 12 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 50 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified of HRO what ecografia on a column of silica gel (1:5 EtOAc:hexane to EtOAc) to obtain (S)-3-(2',2',5'-TriMetrix-4'-enoyl)aminocaproate in the form of a waxy solid (3,g; 84%); melting point 43-44°C;(c = 1, CHCl3) +23,2; nmax/cm-13394, 3251 (NH), 1674, 1633 (CO), 1503 (NH); dH(500 MHz, CDCl3) 7,11 (1H, d,J5,0, CHNH), 6,65-of 6.45 (1H, SIRM, CH2NH), 5,04 (1H, t,Jof 7.5, CH=C), of 4.44 (1H, DDD,J11, 5,5, 1,5, CHNH), 3,24-and 3.16 (2H, m, CH2NH), of 2.20 (1H, DD,J14,5, 7,5, C=CHCH2), to 2.15 (1H, DD,Jthat 14.5 and 7.5, C=CHCH2), 2,03-1,90 (2H, m, 2 × ring CH), 1,84-1,72 (2H, m, 2 × ring CH), of 1.65 (3H, s, CH3), and 1.56 (3H, s, CH3), 1,45 of 1.28 (2H, m, 2 × ring CH), of 1.13 (3H, s, CH3) and 1.12 (3H, s, CH3); dC(125 MHz, CDCl3) 176,9, 176,0 (CO), 134,1, 119,9 (CH=CH), 52,1 (NHCHCO), 42,5 (CH2SEEe2), 42,1 (CH2N), 39,0, 31,5, 28,9, 28,0 (CH2lactam), 26,0, 25,0, 24,9, 17,9 (CH3); m/z (MN+C15H27N2O2requires 267,2073) 267,2063.

Example 24: (S)-3-(2',2',5'-trimethylhexanoyl)aminocaproate: (S)-3-(2',2',5'-trimethylene-4'-enoyl)aminocaproate (400 mg) was dissolved in EtOAc (25 ml), added palladium hydroxide on carbon (20%, about 100 mg) and the mixture mixes with the ambient temperature in an atmosphere of hydrogen for 14 h Then the reaction mixture was filtered through a layer of Celite® and the solvent is removed in vacuo to obtain (S)-3-(2',2',5'-trimethylhexanoyl)aminocaproate in the form of waxy solid (400 mg, 98%); melting point 73-74°C.(c = 1, CHCl3) +27,8; nmax/cm-13249 (NH), 1654, 1638 (CO), 1502 (NH; dH(500 MHz, CDCl3) was 7.08 (1H, d,J5,0, CHNH), 6,75-6,55 (1H, SIRM, CH2NH), of 4.44 (1H, DDD,J11, 5,5, 1,5, CHNH), 3,29-and 3.16 (2H, m, CH2NH), 2,03 is 1.91 (2H, m, 2 × ring CH), 1,84-of 1.73 (2H, m, 2 × ring CH), 1,47 of 1.28 (5H, m, 2 × ring CH + CH2+ CH(CH3)2), of 1.13 (3H, s, CH3), of 1.12 (3H, s, CH3), 1,08-1,02 (2H, m, CH2), of 0.82 (3H, s, CH3), to 0.80 (3H, s, CH3); dC(125 MHz, CDCl3) 177,1, 176,1 (CO), 52,1 (NHCHCO), 42,1 (CH2N)41,9 (CH2SEEe2), 39,0, 33,7, 31,5, 28,9 (CH2), 28,4 (Me2CH)of 27.9 (CH2), 25,3, 25,2, 22,6, 22,5 (CH3); m/z (MN+C15H29N2O2requires 269,2229) 269,2219.

Example 25: (S)-3-(11'-bromoundecanoic)aminocaproate:

Hydrochloride (S)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (25 ml) was added to a solution of 11-bromoundecanoic (5 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture stirred for 4 h the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain(S)-3-(11'-bromoundecanoic)aminocaproate(1,49 g; 79%); melting point (EtOAc) 73-74°C;(c = 1, CHCl3) +31,8; nmax/cm-13342, 3287 (NH), 1668, 1634 (CO), 1515 (NH); dH(500 MHz, d 6-DMSO) 7,76 (1H, t,J6,5, CH2NH), to 7.67 (1H, d,J7, CHNH), to 4.38 (1H, DD,J11, 7, CHNH), 3,51 (2H, t,J6,5, CH2Br,)and 3.15 (1H, DDD,J15,5, 10,5, 5, CHHNH), 3,05 (1H, dt,J14, 7, CHHNH), 2,17-to 2.06 (2H, m, CH2CONH), of 1.85 (1H, dt,J14, 3, C-5 H), 1,82 by 1.68 (4H, m, C-4 H, C-6 H and CH2CH2Br,), of 1.62 (1H, CT,J12, 3,5, C-5 H)of 1.46 (2H, SirkinJ6,5, CH2CH2CONH), 1,41 to 1.31 (3H, m, C-4 H, and the chain CH2) and 1.31-1,13 (11H, m, (CH2)5+ C-6 H); dC(125 MHz, d6-DMSO) of 174.4 (CO-ring), is 171.3 (CO-chain), 51,3 (NHCHCO), 40,7 (NCH2), 35,3, 35,2, 32,4, 31,3, 29,0, 28,9 (×3), 28,7, 28,2, 27,8, 27,6 and 25.4 (CH2); m/z (MN+BrC17H32N2O2requires 375,1647) 375,1655.

Example 26: (S)-3-(11'-azidoaniline)aminocaproate:

Sodium azide (650 mg, 10 mmol) are added to (S)-3-(11-bromoundecanoic)aminocaproate (375 mg, 1 mmol) in DMF (2 ml) and the mixture is heated at 60°C for 14 h and Then the solvent is removed in vacuo and the residue partitioned between water (20 ml) and EtOAc (3 x 20 ml). The combined organic layers are washed with 1 M HClaq(2 x 20 ml) and then dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain(S)-3-(11'-azidoaniline)aminocaproate(221 mg; 66%); melting point (EtOAc) 71-72°C;(c = 1, CHCl3) +34,7; nmax/cm-13344, 3289 (NH), 2101 (N3) 1668, 1631 (CO), 1516 (NH); dH(500 MHz, d6-DMSO) to 7.77 (1H, is, J6, CH2NH), to 7.67 (1H, d,J7, CHNH), to 4.38 (1H, DD,J11, 7, CHNH), 3,30 (2H, t,J7, CH2N3)and 3.15 (1H, DDD,J15,5, 10,5, 5, CHHNH), 3,05 (1H, dt,J14, 5,5, CHHNH), 2,17-2,07 (2H, m, CH2CONH), of 1.85 (1H, dt,J14, 3,5, C-5 H), 1,82 by 1.68 (2H, m, C-4 H, C-6 H)of 1.62 (1H, CT,J13, 3,5, C-5 H)and 1.51 (4H, m, CH2CH2CONH and CH2CH2N3), of 1.36 (1H, CD,J13, 3, C-4 H), and 1,33-1,13 (13H, m, (CH2)6+ C-6 H); dC(125 MHz, d6-DMSO) of 174.4 (CO-ring), is 171.3 (CO-chain), 51,3 (NHCHCO), at 50.7 (CH2N3), 40,7 (NCH2), 35,3, 31,3, 29,0 (×2), 28,9, 28,7, 28,6, 28,3, 27,8, 26,2 and 25.4 (CH2); m/z (MPa+C17H31N5O2Na requires 360,2375) 360,2360.

Example 27: (S) 11'-sulfoacetate sodium-3-(undecanoyl)aminocaproate:

Sodium sulfite (630 mg, 5 mmol) in water (3 ml) are added to (S)-3-(11-bromoundecanoic)aminocaproate (375 mg, 1 mmol) in ethanol (2 ml) and the mixture refluxed for 14 h the Cooled reaction mixture is then added to ethanol (25 ml) and the reaction mixture is filtered. Then the solvent is removed in vacuum to obtain(S) 11'-sulfoacetate sodium-3-(undecanoyl)aminocaproate(456 mg; 97%); melting point (EtOAc) 208-210°C;(c = 1, H2O) -15,5; nmax/cm-13430, 3344, 3289 (NH + H2O), 1667, 1643 (CO), 1530 (NH) 1195, 1183 (CO3, asymmetric.), 1064 (CO3, symmetric.); dH(500 MHz, d6-D IS WITH) 7,76 (1H, t,J6, CH2NH), of 7.70 (1H, d,J7, CHNH), 4,35 (1H, DD,J10, 7,5, CHNH), 3,42 (8H, s, 4 × H2O) 3,17-of 3.00 (2H, m, CH2NH), 2,47-of 2.38 (2H, m, CH2CO3), 2,17-of 2.05 (2H, m, CH2CONH), is 1.82 (1H, Sirs,J13,5, C-5 H), 1,75-of 1.66 (2H, m, C-4 H, C-6 H), 1,65 of 1.50 (3H, m, C-5 H + chain CH2), 1,47-of 1.40 (2H, m, chain CH2) to 1.35 (1H, CD,J13, 3, C-4 H), and 1,30-1,11 (13H, m, (CH2)6+ C-6 H); dC(125 MHz, d6-DMSO) of 174.5 (CO-ring), which is 171,5 (CO-chain), 51,6 (CH2CO3), 51,4 (NHCHCO)and 40.8 (NCH2), 35,3, 31,3, 29,1 (×3), 29,0 (×2), 28,8, 28,6, 27,8, 25,5 and 25.1 (CH2); m/z (MPa+C17H31N2O5SNa2requires 421,1749) 421,1748.

Example 28: (S)-3-(decanesulfonate)aminocaproate:

Hydrochloride (S)-3-aminocaproate (3 mmol) and Na2CO3(9 mmol) in water (20 ml) are added to a solution of decanesulfonate (3 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred for 10 hours and Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc/hexanol to obtain(S)-3-(decanesulfonate)aminocaproate(481 mg; 48%); melting point of 98-99°C;(c = 1, Meon) +22,7; nmax/cm-13365, 3248 (NH), 1657 (CO), 1324, 1142 (SO2N); dH(500 MHz, CDCl3) 6,3-6,18 (1H, m, CH2NH), 5,71 (1H, d,J6, CHNH), 4,11 (1H, DDD,J11,5, 6, 2, CHNH), 3,31-3,18 (2H, m, CH2NH), 2,98 of 2.92 (2H, m, CH2CO2), is 2.09 (1H, shirt,J14, ring CH), 2.06 to of 1.97 (1H, m, ring CH), 1,88-to 1.59 (5H, m, CH2CH2SO2+ 3 ring CH), USD 1.43 and 1.33 (3H, m, chain CH2+ ring CH), 1,32-of 1.18 (12H, m, CH3(CH2)6and 0,86 (3H, m, CH3); dC(125 MHz, CDCl3) 174,8 (CO) 55,5 (NHCHCO), 53,5 (CH2CO2), 40,7 (NCH2), 33,9, 31,8, 29,4, 29,3, 29,2, 29,1, 28,6, 28,3, 27,9, 23,5, 22,6 (CH2) and 14.1 (CH3); m/z (MPa+C16H32N2O3SNa requires 355,2031) 355,2054; the analysis. (C16H32N2O3S requires C, 57,8, H, 9,7, N, 8,4) C, 57,8, H, 9,7, N, 8,3.

Example 29: (S)-3-(dodecanesulfonyl)aminocaproate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (20 ml) are added to a solution of dodecanesulfonate (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred for 10 hours and Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (hexane:EtOAc 3:1 to 100% EtOAc) and then by recrystallization from heptane to obtain(S)-3-(dodecanesulfonyl)aminocaproate(302 mg; 42%); melting point 00-101°C; (c = 1, Meon) +22,4; nmax/cm-13366, 3247 (NH), 1657 (CO), 1324, 1143 (SO2N); dH(500 MHz, CDCl3) of 6.66 (1H, t,J6, CH2NH), 5,78 (1H, d,J6, CHNH), 4,10 (1H, DDD,J11, 6, 2, CHNH), 3,29-3,17 (2H, m, CH2NH), 2,97-2,90 (2H, m, CH2SO2), 2,12-2,03 (1H, m, ring CH), 2,03 is 1.96 (1H, m, ring CH), 1,88-to 1.59 (5H, m, CH2CH2SO2+ 3 ring CH), 1,43-of 1.32 (3H, m, ring CH + chain CH2), 1,32-1,18 (16H, m) and of 0.85 (3H, m, CH3); dC(125 MHz, CDCl3) 175,0 (CO) 55,5 (NHCHCO), 53,5 (CH2SO2), 42,1 (NCH2), 33,8, 31,8, 29,6 (×2), 29,5, 29,3 (×2), 29,1, 28,6, 28,3, 27,9, 23,5, 22,6 (CH2) and 14.1 (CH3); m/z (MPa+C18H36N2O3SNa requires 383,2339) 383,2351; the analysis. (C18H36N2O3S requires C, 60,0, H, 10,1, N, 7,8) C, 59,9, H, 10,2, N, 7,7.

Example 30: (S)-3-(tetradecanoyl)aminocaproate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (20 ml) are added to a solution of tetradecanoylphorbol (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred for 10 hours and Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (hexane:EtOAc 3:1 to 100% EtOAc) and then Perekrest what Lusatia from heptane to obtain (S)-3-(tetradecanoyl)aminocaproate(373 mg; 48%); melting point 100-101°C;(c = 1, CHCl3) +14,4; nmax/cm-13361, 3250 (NH), 1658 (CO), 1324, 1140 (SO2N); dH(500 MHz, CDCl3) only 6.64 (1H, t,J6, CH2NH), 5,74 (1H, d,J6, CHNH), 4,11 (1H, DDD,J11,5, 6, 2, CHNH), 3,30-3,17 (2H, m, CH2NH), 2,97 of 2.92 (2H, m, CH2SO2), 2,12-2,05 (1H, m, ring CH), 2.05 is is 1.96 (1H, m, ring CH), 1,87-to 1.59 (5H, m, CH2CH2SO2+ 3 ring CH), 1,42-of 1.32 (3H, m, ring CH + chain CH2), 1,32-1,18 (20H, m, chain CH2and 0,86 (3H, m, CH3); dC(125 MHz, CDCl3) 174,9 (CO), 55,5 (NHCHCO), with 53.4 (CH2SO2), 42,2 (NCH2), 33,8, 31,9, 29,6 (×4), 29,5, 29,3 (×2), 29,1, 28,6, 28,3, 27,9, 23,5, 22,7 (CH2) and 14.1 (CH3); m/z (MPa+C20H40N2O3SNa requires 411,2652) 411,2655; the analysis. (C20H40N2O3S requires C, 61,8, H, 10,4, N, 7,2) C, 61,9, H, 10,5, N, 7,2.

Example 31: (S)-3-(hexadecanesulfonyl)aminocaproate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (20 ml) are added to a solution of hexadecanesulfonate (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred for 10 hours and Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in Waco is IU. The residue is purified by chromatography on a column of silica gel (hexane:EtOAc 3:1 to 100% EtOAc) and then by recrystallization from heptane to obtain(S)-3-(hexadecanesulfonyl)aminocaproate(553 mg; 66%); melting point 100-101°C;(c = 1, CHCl3) +14,1; nmax/cm-13356, 3249 (NH), 1659 (CO), 1323, 1140 (SO2N); dH(500 MHz, CDCl3) 6,55 (1H, t,J6, CH2NH), USD 5.76 (1H, d,J6, CHNH), 4,11 (1H, DDD,J11,5, 6, 2, CHNH), 3,30-3,17 (2H, m, CH2NH), to 2.94 (2H, t,J8, CH2SO2), 2,12-2,04 (1H, m, ring CH), 2,04-of 1.97 (1H, m, ring CH), 1,87 is 1.58 (5H, m, CH2CH2SO2+ 3 ring CH), 1,42-of 1.32 (3H, m, ring CH + chain CH2), 1,32-1,18 (24H, m, chain CH2and 0,86 (3H, m, CH3); dC(125 MHz, CDCl3) 174,9 (CO), 55,5 (NHCHCO), 53,5 (CH2SO2), 42,1 (NCH2), 33,8, 31,9, 29,7 (×2), 29,6 (×4), 29,5, 29,3 (×2), 29,1, 28,6, 28,3, 27,9, 23,5, 22,7 (CH2) and 14.1 (CH3); m/z (MPa+C20H40N2O3SNa requires 439,2965) 439,2980; the analysis. (C22H44N2O3S requires C, 63,4, H, 10,6, N, 6,7) C, 63,1, H, 10,6, N, 6,6.

Example 32: (S)-3-(octadecanoyl)aminocaproate:

Hydrochloride (S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (20 ml) are added to a solution of octadecyltrichlorosilane (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred for 10 hours and Then the organic layer is separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel (hexane:EtOAc 3:1 to 100% EtOAc) and then by recrystallization from heptane to obtain(S)-3-(octadecanoyl)aminocaproate(545 mg; 61%); melting point 99-100°C; nmax/cm-13356, 3249 (NH), 1659 (CO), 1323, 1140 (SO2N); dH(500 MHz, CDCl3) x 6.15 (1H, t,J6, CH2NH), 5,69 (1H, d,J6, CHNH), of 4.12 (1H, DDD,J11,5, 6, 2, CHNH), 3,30-3,18 (2H, m, CH2NH), 2,97 of 2.92 (2H, m, CH2CO2), 2,12-2,07 (1H, m, ring CH), 2.06 to of 1.97 (1H, m, ring CH), 1,87-of 1.56 (5H, m, CH2CH2SO2+ 3 ring CH), 1,42-of 1.32 (3H, m, ring CH + chain CH2), 1,32-1,18 (28H, m, chain CH2and 0,86 (3H, m, CH3); m/z (MPa+C24H48N2O3SNa requires 467,3277852) 467,330047.

Example 33: (S)-aminocaproate-glycine-(L)-N(Boc)-tryptophan:

This Tripeptide receive automated solid-phase peptide synthesizer using (S)-aminocaproate at the final stage of the peptide condensation. Mr (relative molecular mass) (calculated) = 471,5110. Observed Mr according to mass spectrometry 471,6. Purity (% TIC (trypsin-inhibiting activity) with a molecular ion peak) = 90%.

Example 34: (S)-aminocaproate-(L)-valine-(L)-desamination:

This Tripeptide get on solid-phase avtomatizirov the NR peptide synthesizer using (S)-aminocaproate at the final stage of the peptide condensation. Mr (calculated) = 398,4600. Observed Mr according to mass spectrometry 398,3. Purity (% TIC (trypsin-inhibiting activity) with a molecular ion peak) = 96%.

Examples 35-38 intermediate compounds that can be used in the synthesis of compounds of the invention:

Example 35:

The intermediate connection

(E)-methyl-2,2-dimethylmaleic-4-ENOAT:

Utility (3.8 M, 10 mmol) are added to a solution of Diisopropylamine (1,42 ml, 10 mmol) in dry THF at -78°C in an atmosphere of N2. The reaction mixture was stirred at -78°C for 20 min and then add methylisobutyl (1,15 ml, 10 mmol). The reaction mixture was stirred at -78°C for 1 h, and then add (E)-Oct-2-unibroue (2,19 g, 10 mmol) and the reaction mixture was allow to warm to ambient temperature for 14 hours, the Reaction solvent is then removed in vacuo and the residue partitioned between aqueous buffer at pH 2 (0.5 M NaHSO4/0.5 M Na2SO4) (100 ml) and hexane (3 x 100 ml). The combined organic layers dried over Na2SO4and the hexane solvent is removed in vacuo to obtain crude (E)-methyl-2,2-dimethylmaleic-4-enoate (purity >90%) of 2.27 g) as a colourless oil; nmax/cm-11734 (CO); dH(400 MHz, CDCl3) 5,42 (1H, shirt,J15, 6,5, CH=CH), and 5.30 (1H, DTT,J15, 7, 1, CH=CH), to 3.64 (3H, s, OCH3), to 2.18 (2H, DD,J7, 1, CH2The IU 2), a 1.96 (2H, shirk,J6,5, CH2CH2CH=CH), 1,35-of 1.20 (10H, m, (CH2)5CH3), to 1.14 (6H, s, C(CH3)2), of 0.87 (3H, t,J6,5, CH2CH3); dC(125 MHz, CDCl3) 178,2 (CO), 134,1, 125,2 (HC=CH), 51,5 (OCH3), was 43.6 (CH2), 42,6 (Me2CCO), 32,6, 31,8, 29,5, 29,1, 29,0 (CH2)is 24.7 (C(CH3) × 2), 22,6 (CH2), 14,1 (CH2CH3); m/z (MN+C15H29N2O2requires 241,2168) 241,2169.

Example 36:

The intermediate connection

(E)-2,2-dimethylmaleic-4-tailhold:

The entire product from the reaction described above is then dissolved in ethanol (50 ml) and added to a solution of NaOH (2.0 g, 50 mmol) in water (25 ml). The mixture is refluxed for 6 hours, allow to cool and the solvent then removed in vacuum. The residue is partitioned between aqueous buffer at pH 2 (0.5 M NaHSO4/0.5 M Na2SO4) (100 ml) and diethyl ether (3 x 100 ml). The combined organic layers dried over Na2CO3and the ether solvent removed in vacuo to obtain crude (E)-2,2-dimethylmaleic-4-ene acid (purity >90%) of 2.27 g) as a colourless oil; dH(400 MHz, CDCl3) 5,46 (1H, shirt,J15, 6,5, CH=CH), to 5.35 (1H, DTT,J15, 7, 1, CH=CH), 2,22 (2H, DD,J7, 1, CH2CME2), to 1.98 (2H, shirk,J6,5, CH2CH2CH=CH), 1,37-1,21 (10H, m, (CH2)5CH3, of 1.17 (6H, s, C(CH3)2), of 0.87 (3H, t,J6,5, CH2CH3).The crude acid was dissolved in dichloromethane (50 ml) and add oxalicacid (3 ml) with a drop of DMF. The reaction mixture was stirred for 1 h and the solvent is removed in vacuo to obtain crude (E)-2,2-dimethylmaleic-4-tailhold, which is used without purification in the next stage.

Example 37:

The intermediate connection

Methyl-2,2,5-trimethylene-4-ENOAT:

Utility (2.9 M, 50 mmol) are added to a solution of Diisopropylamine (7.2 ml, 50 mmol) in dry THF at -78°C in an atmosphere of N2. The reaction mixture was stirred at -78°C for 20 min and then add methylisobutyl (5.7 ml, 50 mmol). The reaction mixture was stirred at -78°C for 1 h, and then add 3-methylbut-2-unibroue (5.8 ml, 50 mmol) and the reaction mixture was allow to warm to ambient temperature for 14 hours, the Reaction solvent is then removed in vacuo and the residue partitioned between aqueous buffer at pH 2 (0.5 M NaHSO4/0.5 M Na2SO4) (100 ml) and hexane (3 x 250 ml). The combined organic layers dried over Na2SO4and the hexane solvent is removed in vacuo to obtain methyl-2,2,5-trimethylene-4-enoate in the form of a colorless oil (6,93 g, 81%); nmax/cm-11732 (CO); dH(400 MHz, CDCl3) 5,04 (1H, Sept,J 7,5, 1,5, CH=C), 3,63 (3H, s, OCH3), of 2.20 (2H, d,J7,5, CHCH2), by 1.68 (3H, Sirs, CH=CMeIU), was 1.58 (3H, Sirs, CH=CMEIU), to 1.14 (6H, s, (CH3)2CO); dC(125 MHz, CDCl3) to 178.4 (CO), 134,1 (Me2C=CH), 119,8 (Me2C=CH), 51,6 (OCH3), 42,8 (Me2CCO), 38,7 (CH2), 25,9, 24,7 (× 2), 17,8 (CCH3); m/z (MN+C10H19O2requires 171,1385) 171,1388.

Example 38:

The intermediate connection

2,2,5-trimethylene-4-tailhold:

Methyl-2,2,5-trimethylene-4-ENOAT (2,74 g, 16 mmol) dissolved in ethanol (50 ml) and added to a solution of NaOH (3.0 g, 75 mmol) in water (35 ml). The mixture is refluxed for 6 hours, allow to cool and the solvent then removed in vacuum. The residue is partitioned between aqueous buffer at pH 2 (0.5 M NaHSO4/0.5 M Na2SO4and simple diethyl ether (3 x 150 ml). The combined organic layers dried over Na2SO4and the ether solvent removed in vacuo to obtain the crude 2,2,5-trimethylene-4-ene acid (purity >95%) as a colourless oil; dH(400 MHz, CDCl3) 5,12 (1H, Sept,Jof 7.5 and 1.5, CH=C), of 2.25 (2H, d,J7,5, CHCH2), 1,71 (3H, Sirs, CH=CMeIU)to 1.60 (3H, Sirs, CH=CMEIU), of 1.18 (6H, s, (CH3)2CO). The crude acid was dissolved in dichloromethane (50 ml) and add oxalicacid (3 ml) with a drop of DMF. The reaction mixture is stirred for which the 1 h and the solvent is removed in vacuo to obtain the crude 2,2,5-trimethylene-4-tailhold, which all used without purification in the next stage.

Example 39:

This connection has two end groups 2,2,6,6-tetramethylheptane acid from both sides. This yields a dimer of the corresponding 2,2-dimethyl compounds of the invention:

(S,S)N,N'-bis-(2'-oxazepan-3'-yl)-2,2,6,6-tetramethylpiperidine:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (2 mmol) and Na2CO3(6 mmol) in water (25 ml) was added to a solution of 2,2,6,6-tetramethylethylenediamine (1 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred for 2 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2CO3and evaporated in vacuum. The residue is purified by recrystallization from EtOAc to obtain (S,S)-dimer (199 mg, 46%); melting point 234-236°C;(c = 1, CHCl3) +29,4; nmax/cm-13379, 3255 (NH), 1683, 1637 (CO), 1507, 1497 (NH); dH(500 MHz, CDCl3) 7,07 (2H, d,J5,5, CHNH), 6.42 per (2H, Sirs, CH2NH), of 4.44 (2H, DDD,J11, 5,5, 1,5, CHNH), 3,31-3,17 (4H, m, CH2NH), 2,04-of 1.94 (4H, m, ring CH), 1,86-of 1.73 (4H, m, ring CH), 1,51 to 1.31 (8H, SIRM, 2 × ring CH + CH2CME2) and 1.12 (14H, m, chain CH2CH2CH2+ SEEe2); dC(125 MHz, CDCl3) 176,9, 1759 (CO), 52,1 (NHCH)42,0 (SEEe2), 42,1, 41,5, 31,5, 28,9, 28,0 (CH2), 25,3, 25,1 (CH3) and 20.0 (CH2); m/z (M+C23H40N4O4requires 436,30496) 436,30437.

Example 40: (S)-3-(1',1'-dimethylaminophenyl)aminocaproate

This connection is a sulfonamidnuyu similar example 12.

Example 41: (S)-3-(2'-propylpentanoic)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (15 ml) are added to a solution of 2-propylpentanoate (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture stirred for 12 h Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2SO4and evaporated in vacuum. The residue is recrystallized from hexane to obtain (S)-3-(2'-propylpentanoic)aminocaproate (1,02 g; 80%); melting point (hexane) 114-118°C;(c = 1, CHCl3) +29,4; nmax/cm-13303 (NH), 1686, 1633 (CO), 1537 (NH); dH(500 MHz, CDCl3) to 6.88 (1H, d,J5,5, CHNH), of 6.52 (1H, Sirs, CH2NH), to 4.52 (1H, DDD,J11, 6, 1,5, CHNH), 3,30-and 3.16 (2H, m, CH2NH), 2,13-2,02 (2H, m, (CH2)2CHCO and lactam ring CH), 2,02-of 1.92 (1H, m, lactam ring CH), 1,86-of 1.74 (2H, m, lactam ring CH ×2), 1,57 of 1.50 (2H, m, lateral TSE is ü CH 2), to 1.42 (1H, shirk,J13,5, 3,5, lactam ring CH), 1,38-of 1.29 (2H, m, lactam ring CH + side chain CH2), 1,29-1,19 (4H, m, side chain CH ×4)to 0.85 (3H, t,J7,5, CH3) and 0.84 (3H, t,J7,5, CH3); dC(125 MHz, CDCl3) 175,8, 175,2 (CO), 51,9 (NHCHCO), or 47.2 (CH), 42,1, 35,3, 35,1, 31,7, 28,9, 27,9, 20,7 (×2) (CH2) and 14.1 (×2) (CH3); m/z (MN+C14H27N2O2requires 255,2073) 255,2083.

Example 42(a): (3S,2'R) and Example 42(b): (3S,2'S)-3-(2'-ethylhexanoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate (5 mmol) and Na2CO3(15 mmol) in water (15 ml) was added to a solution of (+/-) 2-ethylhexanoate (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture stirred for 12 h Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2SO4and evaporated in vacuum. The residue is recrystallized from hexane to obtain a mixture of (3S,2'R) and (3S,2'S)-3-(2'-ethylhexanoyl)aminocaproate (328 mg; 26%).

nmax/cm-13306 (NH), 1686, 1633 (CO), 1537 (NH); dH(500 MHz, CDCl3) 6,89 (2H, d,J5, CHNH, both isomers), 6,53 (2H, Sirs, CH2NH, both isomers), to 4.52 (2H, DDD,J11, 6, 1,5, CHNH, both isomers), 3,30-and 3.16 (4H, m, CH2NH, both isomers), to 2.06 (2H, shirt,J13,5, lactam CH ×2, both isomers), 2,02-of 1.92 (4H, m, (CH2)2 CHCO ×2 and lactam ring CH ×2, both isomers), 1,86-of 1.74 (4H, m, lactam ring CH ×4, both isomers), 1,63 of 1.50 (4H, m, side chain CH2), 1,50-of 1.30 (8H, m, lactam ring CH ×4 + side chain CH2×4, both isomers), 1,30-1,14 (8H, m, side chain CH2×8, both isomers), of 0.85 (3H, t,J7,5, CH3one isomer) and 0.82 (3H, t,J7,5, CH3one isomer); dC(125 MHz, CDCl3) 175,8, 175,1 (CO), 52,0, 51,9 (NHCHCO), 49,3 (×2) (CH), 42,0 (×2), 32,5, 32,3, 31,7 (×2), 29,7 (×2), 28,8 (×2), 27,9 (×2), 26,1, 25,9, 22,7 (×2), 14,0, 13,9 (CH3) and 12.0 (×2) (CH3); m/z (M+C14H26N2O2requires 254,1994) 254,1995.

Example 43: 3,3-diethyldodecanamide acid (intermediate compound)

CuI (2 mmol), trimethylsilane (24 mmol) and methyl-3,3-dimethylacrylate (20 mmol) in THF (25 mmol) is cooled to -15°C and for 1 h add noneligible (24 mmol) in THF (80 ml). The reaction mixture allow to warm to room temperature overnight and then quenched by adding saturated aqueous ammonium chloride. THF is removed in vacuo and the residue distributed between hexane and water. The organic layer is evaporated in vacuum and the crude methyl-3,3-dimethylbutanoate dissolved in ethanol (50 ml). Add KOH (100 mmol) in water (10 ml) and the reaction mixture is refluxed for 18 hours and Then the reaction mixture allow to cool and the solvent is removed in vacuum, the OS is atok partitioned between hexane and water. Then the aqueous layer was acidified to pH 2 aqueous HCl and extracted with a simple diethyl ether. The ether layer is dried over Na2SO4and the solution is then evaporated in vacuum to obtain 3,3-diethyldodecanamide acid in the form of oil (3,47 g, 76%); nmax/cm-11702 (CO); dH(500 MHz, CDCl3) 11,12 (1H, Sirs, OH), of 2.21 (2H, s, CH2CO); 1,32-1,20 (16H, m, (CH2)8), and 1.00 (6H, s, C(CH3)2) and 0.87 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 179,1 (CO),45,9, 42,3 (CH2), 33,2 (C(CH3)2), 31,9, 30,3, 29,6 (×2), 29,3, 27,1 (×2) (C(CH3)2), 24,0, 22,6 (CH2) and 14.1 (CH3); m/z (M+C14H28O2requires 228,2089) 228,2082.

Example 44: 3,3-dimethyldodecylamine (intermediate compound)

3,3-diethyldodecanamide acid (5 mmol) dissolved in CH2Cl2(20 ml) and add oxalicacid (1 ml) and dimethylformamide (1 drop). After 1 h the reaction mixture was evaporated in vacuum to obtain the crude 3,3-dimethyldodecylamine, which is directly used in the synthesis of (S)-3-(3',3'-dimethylcarbamoyl)aminocaproate.

Example 45: (S)-3-(3',3'-dimethylcarbamoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate 2 (5 mmol) and Na2CO3(15 mmol) in water (15 ml) are added to a solution of 3,3-dimethyldodecylamine (5 mmol) in dichloromethane (15 ml) at a temperature of the environment is s and the reaction mixture is stirred for 12 hours. Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2SO4and evaporated in vacuum. The residue is recrystallized from hexane to obtain (S)-3-(3',3'-dimethylcarbamoyl)aminocaproate (1,14 g; 68%). The melting point (hexane) 123-125°C;(c = 1, CHCl3) +28,6; nmax/cm-13279 (NH), 1646 (CO), 1498 (NH); dH(500 MHz, CDCl3) for 6.81 (1H, d,J5,5, CHNH), 6,59-6.42 per (1H, SIRM, CH2NH), 4,50 (1H, DDD,J11, 6, 1,5, CHNH), 3,30-and 3.16 (2H, m, CH2NH), 2,08-2,02 (3H, m, CH2CO + lactam ring CH), 2.00 in 1,90 (1H, m, lactam ring CH), 1,86 is 1.75 (2H, m, lactam ring CH ×2), 1,47 to 1.31 (2H, SIRM, lactam ring CH ×2), 1,30-1,17 (16H, m, (CH2)8), to 0.89 (6H, s, C(CH3)2) and 0.84 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 175,8, to 170.9 (CO), 52,0 (NHCH), 48,4, 42,6, 41,1 (CH2), 33,3 (SEEe2), 31,9, 31,7, 30,4, 29,7, 29,6, 29,3, 28,9, 27,9 (CH2)and 27.3 (×2) (CH3), 24,1, 22,6 (CH2) and 14.1 (CH3); m/z (M+C20H38N2O2requires 338,2933) 338,2928.

Example 46: (E)-ethyl-2-methyldodec-2-ENOAT (intermediate compound)

Decanal (5 mmol) and (carletonville)triphenylphosphorane (10 mmol) dissolved in CH2Cl2(20 ml) and the reaction mixture stirred for 18 hours Then the solvent is removed in vacuo and the residue filter the Ute through a plug of silica gel using 15% diethyl ether in hexano. The collected eluent evaporated under vacuum to obtain (E)-ethyl-2-methyldodec-2-enoate in the form of oil (1,02 g, 88%); nmax/cm-11709 (CO), 1651 (C=C); dH(500 MHz, CDCl3) of 6.73 (1H, TC,Jof 7.5 and 1.5, CH=C), of 4.16 (2H, K,J7, OCH2)by 2.13 (2H, shirk,J7,5, CH2CH=C), of 1.80 (3H, d,J1,5, CH3C=CH), 1,45 to 1.37 (2H, m, chain CH2), 1,32-1,19 (15H, m, (CH2)6+ OCH2CH3and of 0.85 (3H, t,J7, (CH2)8CH3); dC(125 MHz, CDCl3) to 168.3 (CO), 142,4 (CH=C), uniforms, 127.6 (CH=C), 60,3 (OCH2), 31,8, 29,5, 29,4 (×2), 29,3, 28,6, 28,5, 22,6 (CH2), and 14.3, 14.1 and 12,3 (CH3);

m/z (MN+C15H29O2requires 241,2168) 241,2165.

Example 47: (E)-methyldodec-2-ANOVA acid (intermediate compound)

(E)-ethyl-2-methyldodec-2-ENOAT (1,43 mmol) dissolved in ethanol (10 ml) and add KOH (10 mmol) in water (5 ml). The reaction mixture was refluxed for 18 h and then cooled. The solvent is removed in vacuo and the residue partitioned between water and hexane. The aqueous layer was acidified with aqueous HCl and extracted with a simple diethyl ether. A layer of diethyl ether is dried over Na2SO4and evaporated in vacuo to obtain (E)-methyldodec-2-ene acid as a solid (308 mg, >95%); melting point 28-31°C; dH(400 MHz, CDCl3) 6,91 (1H, TC,Jof 7.5 and 1.5, CH=C), to 2.18 (2H, shirk,J7,5, CH2CH=C), is 1.82 (3H, d,J1,5, CH C=CH), 1,48-of 1.39 (2H, m, chain CH2), 1,36-1,19 (12H, m, (CH2)6) and 0.88 (3H, t,J7, (CH2)8CH3) (peak IT is not observed).

Example 48: (E)-2-methyldodec-2-inorganic (intermediate compound)

(E)-2-methyldodec-2-envoy acid (1,43 mmol) dissolved in CH2Cl2(20 ml) and add oxalicacid (1 ml) and dimethylformamide (1 drop). After 1 hour the reaction mixture is evaporated in vacuo to obtain crude (E)-2-methyldodec-2-tailhold, which is directly used in the synthesis of (S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate.

Example 49: (S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate 2 (2 mmol) and Na2CO3(6 mmol) in water (15 ml) was added to a solution of (E)-2-methyldodec-2-tailhold (1,43 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture stirred for 12 h Then the organic layer was separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2SO4and evaporated in vacuum. The residue is recrystallized from hexane to obtain (S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate (297 mg; 65%). The melting point (hexane) 99-100°C; nmax/cm-13282 (NH), 1656, 1622 (CO and C=C), 1497 (NH);(c = 1, CHCl3) +38,2; dH(500 MHz, CDCl ) to 7.15 (1H, d,J5,5, NHCH), 6.48 in to 6.35 (2H, m, NHCH2+ CH=C), of 4.54 (1H, DDD,J11, 5,5, 1,5, NHCH), 3,33-3,17 (2H, m, CH2NH), 2,14-2,05 (3H, m, CH2CH=C + lactam ring CH), 2,02-of 1.93 (1H, m, lactam ring CH), a 1.88-1.77 in (5H, m, lactam ring CH ×2 + CH3C=CH), 1,47 to 1.31 (4H, SIRM, lactam ring CH ×2 + chain CH2), 1,31-1,17 (12H, m, (CH2)6and of 0.85 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 175,9, 168,2 (CO), 136,9 (CH=C), is 130.2 (CH=C), 52,3 (NHCH), 42,2 (NHCH2), 31,8, 31,6, 29,5, 29,4 (×2), 29,3, 28,9, 28,7, 28,3, 27,9, 22,6 (CH2), and 14,1 12,4 (CH3).

Example 50(a): (3S,2'R) and

Example 50(b): (3S,2'S)-3-(2'-methylcatechol)aminocaproate;

(S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate (0.5 mmol) and Pd(OH)2(20% on carbon) is added to methanol (10 ml) and the mixture stirred for 18 h at ambient temperature in a hydrogen atmosphere. The reaction mixture was then filtered and the solvent is removed in vacuum to obtain (3S,2'S)-3-(2'-methylcatechol)aminocaproate in the form of a solid (160 mg, >95%); nmax/cm-13313 (NH), 1671, 1636 (CO), 1515 (NH); dH(500 MHz, CDCl3) 6,91 (2H, d,J5,5, CHNH, both isomers), 6,55 (2H, Sirs, CH2NH, both isomers), 4,57-4,47 (2H, m, CHNH, both isomers), 3,34-3,18 (4H, m, CH2NH, both isomers), 2,29 with 2.14 (2H, CH3CHCO., both isomers), 2,07 (2H, shirt,J13,5, lactam ring CH, both isomers), 2,02-of 1.94 (2H, m, lactam ring CH, the BA isomer), 1,89 to 1.76 (4H, m, lactam ring CH ×2, both isomers), 1,67-of 1.57 (2H, m, chain CH, both isomers), 1,51 and 1.33 (6H, m, lactam ring CH ×2 + side chain CH2, both isomers), 1,32-1,18 (32H, m, (CH2)8, both isomers), of 1.13 (3H, d,J7, CHCH3one isomer), is 1.11 (3H, d,J7, CHCH3one isomer) and 0.87 (6H, t,J7,5, CH3, both isomers); dC(125 MHz, CDCl3) 175,9 (×2), 175,8 (×2) (CO., both isomers), 52,0, 51,9 (NCH), 42,1 (×2) (NCH2, both isomers), 41,3, 41,2 (CHCH3), 34,5, 34,1, 31,9 (×2), 31,8, 31,7, 29,6 (×6), 29,5 (×2), 29,3 (×2), 28,9 (×2), 28,0, 27,9, 27,4 (×2), 22,6 (×2) (CH2) 17,8, and 17,6 14,1 (×2) (CH3); m/z (MN+C19H37N2O2requires 325,2855) 325,2858.

Example 51: (4S,2'S,3'R)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-he (intermediate compound)

This aldorino reaction is carried out according to published methods (Crimmins, M.T.; She, J.; Synlett, 2004, 1371-1374). (S)-4-benzyl-3-propionylcarnitine-2-he (5 mmol) (synthesized according to the method of Evans et al. Tetrahedron Lett., 1987, 28, 1123) was dissolved in CH2Cl2(25 ml) and the solution is cooled to -20°C in dry nitrogen atmosphere and add TiCl4(the 5.25 mmol). After 15 minutes add diisopropylethylamine (5.5 mmol). After another 40 min add N-methylpyrrolidine-2-he (the 5.25 mmol). After another 10 minutes add decanal (5.5 mmol) and the reaction mixture stirred for 1 h Add a solution of ammonium chloride and the reaction cosplaywhat buffer pH 2 (0.5 M Na 2SO4/0,5 M NaHSO4). The organic layer is dried over Na2SO4and evaporated in vacuum. The crude product chromatographic on silica gel (10% to 33% ethyl acetate in hexane) to produce (4S,2'S,3'R)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)-oxazolidin-2-it is in the form of oil (1,34 g, 69%); nmax/cm-11778 (NCO2), 1697 (CON); dH(500 MHz, CDCl3) 7,35-7,30 (2H, m,meta-Ph), 7,29-7,24 (1H, m,pair-Ph), 7,21-7,17 (2H, m,ortho-Ph), 4,69 (1H, DDT,J9,5, 7,5, 3,5, CHN), is 4.21 (1H, t,J9, OCHH)to 4.17 (1H, DD,J9, 3, OCHH), 3,93 (1H, DDD,J7, 4,5, 3, CHOH in), 3.75 (1H, CD,J7, 2,5, CHCH3), 3,24 (1H, DD,J13,5, 3,5, CHHPh), 2,87 (1H, Sirs CHOH), 2,78 (1H, DD,J13,5, 9,5, CHHPh), 1,56-1,20 (19H, m, (CH2)8+ CHCH3and 0,86 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 177,6 (CCO), 153,0 (OCO), 135,0 (ipso-Ph), 129,4, 129,0 (ortho- +meta- Ph), 127,4 (pair-Ph)71,5 (CHOH), 66,1 (OCH2), 55,1 (NCH), 42,1 (CHCH3), 37,8, 33,8, 31,9, 29,6 (×3), 29,3, 26,0, 22,7 (CH2), a 14.1 10.3 (CH3); m/z (MN+C23H36NO4requires 390,2644) 390,2641.

Example 52: (4R,2'R,3'S)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-he (intermediate compound)

R-4-benzyl-3-propionylcarnitine-2-he turned into (4R,2'R,3'S)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-in accordance with the process described above. The NMR spectroscopic data are identical; m/z (MN+C H36NO4requires 390,2644) 390,2638.

Example 53: (2S,3R)-3-hydroxy-2-metalmeccanica acid (intermediate product)

(4R,2'S,3'S)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-he (to 1.42 mmol) dissolved in THF (10 ml). Add water (2 ml), aqueous hydrogen peroxide (8M, 0.5 mmol) and LiOH·H2O (3 mmol) and the reaction mixture stirred for 18 hours Add Na2SO3(10 mmol) and the reaction mixture is extracted with ethyl acetate. Then the aqueous layer was acidified with a buffer at pH 2 (0.5 M Na2SO4/0,5 M NaHSO4) and extracted with diethyl ether. A layer of diethyl ether is dried over Na2SO4and evaporated in vacuo to obtain crude (2S,3R)-3-hydroxy-2-methyldienolone acid; dH(400 MHz, CDCl3) 3,96-to 3.89 (1H, m, CHOH), 2,59 (1H, DK,J7, 3, CHCH3), and 1.54-of 1.36 (2H, m, CH2), 1,36-1,22 (14H, m, (CH2)7) and 1.20 (3H, d,J7, CHCH3). This material is directly used in the synthesis of (3S,2'S,3'R)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate.

Example 54: (2R,3S)-3-hydroxy-2-metalmeccanica acid (intermediate product)

(2R,3S)-3-hydroxy-2-methyldienolone acid is obtained from (4R,2'R,3'S)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-in accordance with the process described above.

Example 55: (3S,2'S,3'R)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate:

(2S,3R)-3-hydroxy-2-methyldienolone acid of 1.40 mmol) was dissolved in Meon (10 ml) and add (S)-3-aminopropionitrile (1.50 mol) and triethylamine (2 mmol). The reaction mixture was cooled to 0°C and add the chloride of 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholine (1,40 mmol). The reaction mixture was stirred for 4 h and then the solvent is removed in vacuum. The residue is distributed between ethyl acetate and water. An ethyl acetate layer is washed with diluted aqueous HCl and dilute aqueous NaOH and then dried over Na2SO4. The solvent is removed in vacuum and the residue is recrystallized from ethyl acetate/hexane to obtain (3S,2'S,3'R)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate in the form of a solid (341 mg, 72%); melting point (hexane) 88-91°C; nmax/cm-13313 (NH), 1628 (CO), 1480 (NH);(c = 0.5, CHCl3) +40,8; dH(500 MHz, CDCl3) was 7.08 (1H, dJ5,5, NHCH), 6,51 (1H, Sirs, NHCH2), of 4.57 (1H, DDD,J11, 6,5, 1, NCH), 3,83 (1H, dt,J8, 4, CHOH), 3,36-is 3.21 (2H, m, NCH2), is 2.40 (1H, DK,J7, 3, CHCH3), 2,12 is 1.96 (2H, m, lactam CH ×2), 1,90 to 1.76 (2H, m, lactam CH ×2), 1.55V is 1.34 (4H, m, lactam CH ×2 + chain CH2), 1,34-1,21 (14H, m, (CH2)7), of 1.17 (3H, d,J7, CHCH3) and 0.88 (3H, t,J7, CH2CH3) (OH not observed); dC(125 MHz, CDCl3) 175,8, 175,7 (CO), 72,1 (CHOH), 52,0 (NCH)and 44.6 (CHCH3), 42,1

(NCH2), 33,4, 31,9, 31,3, 29,6 (×2), 29,5, 29,3, 28,8, 27,9, 26,1, 22,7 (CH2), and 14,1 11,2 (CH3); m/z (MN+C19H37N2O3requires 341,2804) 341,2776.

Example 56: (3S,2'R,3'S)-3-(3'-hydro is si-2'-methyldecyl)aminocaproate:

(2R,3S)-3-hydroxy-2-metalmeccanica acid (1,40 mmol), (S)-3-aminopropionitrile (1.50 mmol), triethylamine (2 mmol) and chloride 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholine (1,40 mmol) interact, as described above, to obtain (3S,2'R,3'S)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate, which is recrystallized from ethyl acetate/hexane (86 mg, 18%); melting point (hexane) 118-121°C; nmax/cm-13294 (NH), 1667, 1613 (CO), 1533 (NH);(c = 0.5, CHCl3) +14,8; dH(500 MHz, CDCl3) 7,11 (1H, d,J6, NHCH), is 6.54 (1H, Sirs, NHCH2), a 4.53 (1H, DDD,J11, 6,5, 1,5, NCH), a 3.87-of 3.80 (1H, m, CHOH), 3,70 (1H, Sirs, OH), 3,34-3,20 (2H, m, NCH2), is 2.37 (1H, DK,J7, 3, CHCH3), 2,11 is 1.96 (2H, m, lactam CH ×2), 1,90 to 1.76 (2H, m, lactam CH ×2), 1,55-1,21 (18H, m, lactam CH ×2 + chain (CH2)8), of 1.16 (3H, d,J7, CHCH3) and 0.88 (3H, t,J7, CH2CH3); dC(125 MHz, CDCl3) 175,9, 175,7 (CO), 72,0 (CHOH), 52,1 (NCH), 44,8 (CHCH3), 42,1 (NCH2), 33,7, 31,9, 31,4, 29,6 (×2), 29,5, 29,3, 28,8, 27,9, 26,0, 22,7 (CH2), and 14,1 10,7 (CH3); m/z (MN+C19H37N2O3requires 341,2804) 341,2803.

Example 57: Methyl-2,2-dimethyl-3-hydroxydecanoate (intermediate compound)

Utility (2.5 M in hexano, 50 mmol) are added to a solution of Diisopropylamine (50 mmol) in dry THF at -78°C in an atmosphere of dry nitrogen. The reaction mixture was stirred for 30 min and ZAT is m add methylisobutyl (50 mmol). After 45 minutes add decanal (50 mmol) and the reaction mixture was allow to warm to ambient temperature for 18 hours After addition of saturated aqueous ammonium chloride (10 ml), the reaction solvent is removed in vacuo and the residue distributed between hexane and aqueous buffer at pH 2 (0.5 M NaHSO4/0.5 M Na2SO4). The organic layer is dried over Na2SO4and the solvent is removed to obtain methyl 2,2-dimethyl-3-hydroxydecanoate in the form of oil (9,98 g, 77%); dH(400 MHz, CDCl3) 3,70 (3H, s, OCH3), of 3.69 (1H, DD,J10, 2, CHOH), 1,68-1,20 (16H, m, (CH2)8), to 1.19 (3H, s, CCH3), of 1.17 (3H, s, CCH3) and 0.88 (3H, t,J7, CH2CH3) (IT is not observed).

Example 58: 2,2-dimethyl-3-hydroxydecanoic acid (intermediate compound)

Methyl-2,2-dimethyl-3-hydroxydecanoate (20 mmol) dissolved in EtOH (80 ml) and add a solution of KOH (40 mmol) in water (20 ml). The reaction mixture was refluxed for 18 h and then the reaction mixture allow to cool. The solution is removed under vacuum and the residue partitioned between water and diethyl ether. The aqueous layer was then acidified with a buffer at pH 2 (0.5 M Na2SO4/0,5 M NaHSO4) and extracted with diethyl ether. The solution is dried over Na2CO4and evaporated in vacuum to obtain 2,2-dimethyl-3-hydroxydecanoic sour is s, which solidified upon standing; melting point 39-41°C; dH(400 MHz, CDCl3) to 3.64 (1H, DD,J10, 2, CHOH), 1,67-1,12 (22H, m, (CH2)8+ C(CH3)2) and 0.88 (3H, t,J7, CH2CH3).

Example 59(a): (3S,3'R) and

Example 59(b): (3S,3'S)-3-(3'-hydroxy-2',2'-dimethylbutanol)aminocaproate:

2,2-dimethyl-3-hydroxydecanoic acid (1.77 mmol) and 1-hydroxybenzotriazole (1.77 mmol) dissolved in THF (10 ml). Add the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.77 mmol) and the reaction mixture stirred at ambient temperature for 4 hours Add a solution of hydroperoxides-5-carboxylate (S,S)-3-aminocaproate 2 (2 mmol) and Na2CO3(6 mmol) in water (15 ml) and the reaction mixture stirred for 18 hours, the Reaction solvent is then removed in vacuo and the residue partitioned between water and ethyl acetate. An ethyl acetate layer is washed with buffer at pH 2 (0.5 M NaHSO4/0.5 M Na2SO4) and dilute aqueous sodium hydroxide and then dried over Na2SO4and evaporated in vacuum. The remainder chromatographic on silica gel (25% ethyl acetate in hexano to 100% ethyl acetate) to obtain a mixture of (3S,3'R) and (3S,3'S)-3-(3'-hydroxy-2',2'-dimethylbutanol)aminocaproate (557 mg, 88%); dH(500 MHz, CDCl3) 7,28 (1H, d,J6, NHCH, one isomer), 7,25 (1H, d,J6, NHCH, one of the measures), 6,62-6,48 (1H, SIRM, NHCH2, both isomers), 4,53 was 4.42 (1H, m, NCH, both isomers), of 3.77 (1H, shirt,J, 6, OH, one isomer), 3,63 (1H, shirt,J, 6, OH, one isomer), 3,47-to 3.36 (1H, m, CHOH, both isomers), 3,32-3,17 (2H, m, NCH2, both isomers), 2,07-of 1.92 (2H, m, lactam CH ×2, both isomers), 1,87-1,71 (2H, m, lactam CH ×2, both isomers), 1,60-1,17 (21H, m, lactam CH ×2 + chain (CH2)8+ CH3, both isomers), to 1.14 (3H, s, CCH3both isomer) and 0.84 (3H, t,J7, CH2CH3, both isomers); dC(125 MHz, CDCl3) 177,6, 177,2, 175,8 (CO, both isomers), 77,8, 77,4 (CHOH), 52,1 (NCH, both isomers), 45,9, 45,8 (C(CH3)2), 42,1, 42,0 (NCH2), 31,9 (×2) 31,6, 31,3, 30,9, 29,6 (×4), 29,3, 28,8, 27,9, 26,7, 26,6, 22,6 (CH2), 23,7, 23,5, 21,1, 20.4% and 14,1 (CH3).

Example 60: 2,2-dimethyl-3-(tetrahydropyran-2-yloxy)propionic acid (intermediate compound)

2,2-dimethyl-3-hydroxypropionic acid (100 mmol) and 3,4-dihydro-2H-Piran (210 mmol) dissolved in dichloromethane (50 ml) and add a pair of toluensulfonate acid (10 mg) and the reaction mixture stirred at ambient temperature for 3 hours, the Reaction solvent is then removed and the residue is dissolved in ethanol (100 ml). Add a solution of KOH (120 mmol) in water (30 ml) and the reaction mixture is refluxed for 18 hours, the Reaction solvent is removed in vacuo and the residue partitioned between water and diethyl ether. The aqueous layer was then acidified b is from at pH 2 (0.5 M Na 2SO4/0,5 M NaHSO4) and then extracted with diethyl ether. A layer of diethyl ether then dried over Na2SO4and rectorial removed in vacuum to obtain 2,2-dimethyl-3-(tetrahydropyran-2-yloxy)propionic acid in the form of oil (20,0 g, >95%); dH(400 MHz, CDCl3) to 4.62 (1H, t,J3,5 CHO2), 3,82 (1H, DDD,J12, 9, 3, ring CH2O in), 3.75 (1H, d,J12, the chain CH2O), 3,55-of 3.46 (1H, m, ring CH2O), 3,40 (1H, d,J12, the chain CH2O), 1,90-of 1.45 (6H, m, (CH2)3), 1,25 (3H, s, CH3and of 1.23 (3H, s, CH3).

Example 61: (S)-(2',2'-dimethyl-3'-hydroxypropionic)aminocaproate:

2,2-dimethyl-3-(tetrahydropyran-2-yloxy)propionic acid (4,65 mmol), 1-hydroxybenzotriazole (4,65 mmol) and carbonyldiimidazole (4,50 mmol) dissolved in THF (30 ml) and the reaction mixture is refluxed for 4 hours, After cooling the reaction mixture to ambient temperature, add a solution of hydroperoxides-5-carboxylate (S,S)-3-aminocaproate 2 (5 mmol) and Na2CO3(15 mmol) in water (30 ml) and the reaction mixture stirred for 18 hours Then THF is removed from the reaction mixture by distillation in vacuo and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer is dried over Na2SO4and evaporated in vacuum. The residue is dissolved in Meon and add acetylchloride (1 ml). The reaction mixture was stirred at t is mperature environment for 18 h and then evaporated in vacuo to obtain (S)-(2'2'-dimethyl-3'-hydroxypropionic)aminocaproate in the form of solids (854 mg, 83%); melting point 97-99°C;(c = 0.5, CHCl3) +30,0; dH(400 MHz, CDCl3) of 7.24 (1H, d,J5,0, CHNH), 6,38 (1H, Sirs, CH2NH), of 4.49 (1H, DD,J10, 6, CHNH), of 3.54 (1H, d,J11, CHHOH), 3,49 (1H, d,J11, CHHOH), 3,33-3,20 (2H, m, CH2NH), 2,03 is 1.96 (2H, m, 2 × ring CH), 1,87-1,72 (2H, m, 2 × ring CH), 1,50-of 1.30 (2H, m, 2 × ring CH), 1,20 (3H, s, CH3) and 1.18 (3H, s, CH3); dC(125 MHz, CDCl3) 177,2, 176,0 (CO)69,9 (CHOH), 52,1 (NHCHCO), 43,2 (CCO), 41,9 (CH2N), 31,1, 28,8 of 27.9 (CH2lactam), and 22,4 22,3 (CH3).

Example 62:(S)-(3'-chloro-2'-(chloromethyl)-2'-methylpropionyl)aminocaproate:

Hydropyridine-5-carboxylate (S,S)-3-aminocaproate 2 (5 mmol) and Na2CO3(15 mmol) in water (15 ml) are added to a solution of 3,3'-dichlorphenamide (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture is stirred for 12 hours the Organic layer is then separated and the aqueous phase extracted with additional dichloromethane (2 x 25 ml). The combined organic layers dried over Na2SO4and evaporated in vacuum. The residue is purified by recrystallization from hexane to obtain (S)-(3'-chloro-2'-(chloromethyl)-2'-methylpropionyl)aminocaproate (973 mg; 69%); melting point (hexane) 95-96°C.(c = 0.5, CHCl3) +16,4; dH(500 MHz, CDCl3) 7,33 (1H, d,J5,0, CHNH), 6,82-6,62 (1H, SIRM, CH2NH), of 4.49 (1H, d is d, J11, 5,5, 1,5, CHNH), of 3.78 (1H, d,J11, CHHCl), 3,74 (1H, d,J11, CHHCl), of 3.69 (1H, d,J11, CHHCl), 3,66 (1H, d,J11, CHHCl), 3,29-3,17 (2H, m, CH2NH), was 2.05 (1H, Sirs,J13,5, ring CH), 2,01-of 1.93 (1H, m, ring CH), 1,87-1,71 (2H, m, 2 × ring CH) and 1,49 to 1.31 (5H, m, 2 × ring CH + CH3); dC(125 MHz, CDCl3) 175,4, 170,6 (CO), 52,6 (NHCHCO), 49,1 (CCO), 48,7, to 48.6 (CH2Cl), 42,1 (CH2N), 31,1, 28,8 of 27.9 (CH2lactam) and 18.9 (CH3).

Pharmacological study of the products of the invention

The inhibition induced MCP-1 migration of leukocytes

The principle of analysis

The biological activity of the compounds of the present invention can be demonstrated using any of a wide range of functional analyses of the migration of leukocytes in vitro, including, but not limited to, the camera Boyden and related analyses migration through the hole, analyses of migration under agarose and camera direct visualization, such as Luggage Dunn.

For example, to demonstrate the inhibition of the migration of leukocytes in response to chemokines (but not other chemoattractant) used the analysis system migration through the hole in the format of a 96-well microplate from Neuroprobe (Gaithersburg, MD, USA). In principle, this analysis consists of two chambers separated by a porous membrane. The chemoattractant is placed in the lower compartment, and the cells placed in the upper compartment. After incubation for some is the second period at 37°C. cells moving in the direction of chemoattractant, and the number of cells in the lower compartment in proportion to the activity of chemoattractant (relative to a series of controls).

This analysis can be used with a range of different populations of leukocytes. For example, you can use freshly prepared peripheral blood leukocytes of man. Alternatively, you can get a subpopulation of leukocytes, including polymorphically cells or monocytes, using methods well-known to specialists in this field, such as centrifugation in density gradient or magnetic separation beads. Alternatively, you can use the immortal line of cells that were widely accepted as models of leukocytes in human peripheral blood, including, but not limited to, cells TNR-1, as a model of monocytes, or cells of Jurkat as a model of intact T cells.

Although the acceptable range of conditions for analysis with the aim of demonstrating the inhibition caused by the chemokine migration of leukocytes, here is a specific example.

Material

Analysis system migration through the hole made Neuroprobe, Gaithersburg, MD, USA.

Used tablets are tablets ChemoTx (Neuroprobe 101-8) and 30 ál of transparent plates (Neuroprobe MP-30).

Balanced salt solution Gey purchased from Sigma (Sigma G-9779).

Free fatty acid BSA (bovine, cyberotic the initial albumin) purchased from Sigma (Sigma A-8806).

MTT, i.e. bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium purchased from Sigma (Sigma M-5655).

RPMI-1640 without phenol red purchased from Sigma (Sigma R-8755).

Cell line TNR-1 (European collection of cell cultures) use as a cell population of cells.

The test Protocol

The following procedure is used to test the compounds according to the invention for detecting the migration of leukocytes induced MCP-1:

First, get the cell suspension, which is designed to be placed in the upper compartment. Cells TNR-1 precipitated by centrifugation (770 x g, 4 min) and washed with balanced salt solution Gace with 1 mg/MLM BSA (GBSS + BSA). Then this washing is repeated, and the cells re-precipitated before resuspending in a small amount of GBSS + BSA to calculate, for example, using standard hemocytometer.

Then the amount of GBSS + BSA adjusted depending on the number of cells present, so that the cells present in the target area 4.45 x 106cells in 1 ml of GBSS + BSA. This ensures that there are 100,000 cells TNR-1 in every 25 μl of the solution, which should be placed in the upper chamber tablets.

For testing a single connection to its ability to inhibit migration induced MCP-1, you get 2 lots of cells. Cell suspension TNR-1 at a concentration of 4.45 x 106cells/ml delete 2 of the vessel. In a pot add the test inhibitor in the relevant final concentration in the media (for example, in quantities of 1 μm in 1% DMSO). The second vessel adds an equal amount of GBSS + BSA plus media (for example, not more than 1% DMSO) to act as a control.

Then get the solution chemoattractant designed to be placed in the lower compartment. MCP-1 was diluted in GBSS + BSA to obtain a final concentration of 25 ng/ml of This solution is divided into two vessels, as for the cell suspension. In a pot add the test connection to the same final concentration as added to the cell suspension, while in another vessel add the corresponding equal amount of GBSS + BSA plus media (for example, not more than 1% DMSO).

It should be noted that when establishing a final concentration of MCP-1 in the solution for the lower compartment and the final concentration of the cells in the upper compartment should take into account the volume of liquid that is required to add the test connection.

After obtaining solutions chemoattractant to the bottom of the hole and cellular solutions for top cameras should be collected chamber migration. Place 29 μl of a solution of the corresponding chemoattractant in the lower well of the chamber. Tests should be performed at least three times definition wide-angle the mi of each state. After filling in all the lower chambers to cause the porous membrane at the camera in accordance with the manufacturer's instructions. Finally, apply 25 μl of each cell solution to each upper chamber. To prevent evaporation on the entire device, put the plastic cover.

The collected camera incubated at 37°C, 5% CO2within 2 hours, the Suspension of cells in GBSS + BSA also incubated under identical conditions in vitro: these cells are used to plot a standard curve to determine the number of cells that migrated to the lower chamber at each condition.

At the end of the incubation liquid cell suspension carefully removed from the upper chamber and the upper chamber add 20 ál of ice-cold 20 mm EDTA in PBS and the device is incubated at 4°C for 15 minutes, This procedure causes a drop in the lower chamber of any of the cells adhering to the underside of the membrane. After this incubation, the filter gently rinse GBSS + BSA for leaching EDTA and then the filter is removed.

The number of cells that migrated to the lower chamber in each condition, can then be determined in a number of ways, including direct counting, label, fluorescent or radioactive markers and through the use of vital dye. Usually, the applicants are using the vital dye MTT. 3 μl of MTT stock solution added to each well and the eat the plate incubated at 37°C for 1-2 h, and at this time dehydrogenase enzymes inside the cells convert the soluble MTT to insoluble blue product formazan, which can be quantitatively characterized spectrophotometrically.

Parallel build 8-point standard curve. Since the number of cells added to each upper chamber (100000), and descending double serial dilutions in GBSS + BSA, cells are added to the plate 25 ál by adding 3 μl of MTT stock solution.

The tablet standard curve incubated along with plansyou migration.

At the end of this incubation, the liquid is carefully removed from the bottom of the camera, observing precautions in order to avoid violations of the besieged formisano product. After allowing a short drying air in each of the bottom camera add 20 ál of DMSO to dissolve the blue dye and determine the spectral absorption capacity at 595 nm using a card reader 96-well plate. Then the spectral absorption capacity of each well interpolate on the standard curve to estimate the number of cells in each lower chamber.

Stimulated migration of MCP-1 is determined by subtracting the average number of cells that reached the lower compartment in the holes where not added MCP-1, average number of cells that reached the bottom the first compartment, attended by MCP-1 in a concentration of 25 ng/ml

The effect of the test substance is calculated by comparing the induced MCP-1 migration, which took place in the presence or absence of various concentrations of the test substance. Typically the inhibition of migration is expressed as a percentage of total induced MCP-1 migration, which was blocked by the presence of the connection. For most compounds graph of dose-response build definition inhibition induced MCP-1 migration, which occurs in a range of different concentrations of compounds (usually in the range from 1 nm to 1 μm or above in the case of compounds with low activity). Then the inhibitory activity of each compound is expressed as the concentration of the compound required to reduce by 50% caused by MCP-1 migration (the concentration of the ED50).

Results

Were tested compounds of examples 1-7 and 9-34 and 39, 41, 42, 45, 49, 50, 55, 56, 61 and 62, and it was shown that in this test of their ED50made 100 nm or less.

Enantioselectivity

Synthesized (S)- and (R)-enantiomers of three different members of aminocaproate series to determine, does the biological activity of enantioselectivity.

Were compared compounds of examples 1 and 7, the compounds of examples 10 and 11 and the compounds of examples 12 and 17.

Curves depend the value of dose-response for each of the four compounds of examples 1, 7, 10 and 11 as inhibitors of cell migration TNR-1 induced MCP-1 was determined using analysis of migration through the hole, and the results are shown in the drawing. In both cases, (S)-enantiomer was significantly (10-50 times more active than (R)-enantiomer. Very similar data were obtained using the compounds of examples 12 and 17, so that (S)-enantiomer was significantly (10-50 times more active than (R)-enantiomer.

These data on the three representatives of examples aminocaproate series demonstrate that the use of the compounds in accordance with the present invention as anti-inflammatory drugs in vivo, it is preferable to use pure (S)-enantiomer of the compound, and not a racemic mixture of two enantiomers or pure (R)-enantiomer.

The activity in vivo of the compounds in accordance with the invention:

Anti-inflammatory activity of the compounds according to the invention was determined in vivo using a model of sublethal endotoxemia caused by LPS (lipopolysaccharide). Adult male mice CD-1 (n=6 per group) was pre-treated with various agents (media, compounds in accordance with the invention, or agents of the positive control, such as steroid desametasone) subcutaneous injection 30 minutes before acute inflammatory provocative sample of 750 µg of bacterial lipopolysaccharide (E. coli 111:B4; Sigma catalog #L-4130) by intraperitoneal. The medium in each case was of 0.6% DMSO, 1% carboxymethylcellulose or alternative 1% carboxymethylcellulose. For some of the compounds of this composition yields a finely ground suspension or slurry, is not a clear solution. After 2 h after provocative test with LPS animals were killed and blood was sucked out by cardiac puncture. The level of proinflammatory cytokine TNF-alpha were determined using Quantikine M ELISA (R&D Systems) for murine TNF-alpha and the results were presented as average values ± standard error for each group.

The mice that did not receive a provocative test with LPS, were very low circulating levels of TNF-alpha (usually 10 PCG/ml). To 2 h after a provocative test with LPS they increased more than 1000 times to an average of 20000 PCG/ml, representing a sensitive indicator of inflammatory activation. Pre-treatment anti-inflammatory drugs (such as steroid dexamethasone) reduced the stimulation of TNF-alpha by up to 85-95%, depending on the administered dose.

All compounds 7, 9, 10, 12 and 20 were tested on this model. All five compounds were able to block the stimulation of TNF-alpha are similar to dexamethasone extent with the introduction of a suitable dose. All five compounds were maximally active at a dose below 1 is g/kg

In a separate series of experiments, the compounds according to the invention was administered to the animals in the form of a suspension for oral administration prepared in the same manner as for experiments subcutaneous injection, after 1 hour, after which followed a provocative test with LPS, exactly as described above. On this model have been tested compounds 7, 9, 10, 12 and 20, and all 5 compounds were able to block the stimulation of TNF-alpha when ingested by a suitable dose. All five compounds were maximally active at a dose lower than 30 mg/kg

1. The derived 3-aminocaproate formula (I)

where X represents a-CO-R1or-SO2-R2,
R1represents alkyl (except 5-methylheptane and 6-methylheptane, where the radical R1attached to the carbonyl at position 1), allogeneically, alkoxy (except tert-Butylochka), alkanniny, alkynylaryl or alkylamino radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms), and
R2represents an alkyl radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 atoms of plastics technology : turning & the Yes, 13-18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms);
or its pharmaceutically acceptable salt.

2. The compound of formula (I')
,
where X has the meaning given in claim 1, or its pharmaceutically acceptable salt.

3. Pharmaceutical composition having anti-inflammatory activity, comprising as active ingredient a compound of the formula (I) or its pharmaceutically acceptable salt

where X represents a-CO-R1or-SO2-R2,
R1represents alkyl (except 5-methylheptane and 6-methylheptane, where the radical R1attached to the carbonyl at position 1), allogeneically, alkoxy (except tert-Butylochka), alkanniny, alkynylaryl or alkylamino radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms), and
R2represents an alkyl radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms);
and at least one pharmaceutically acceptable excipient and/or but Icel.

4. Pharmaceutical composition having anti-inflammatory activity, comprising as active ingredient a compound of the formula (I') or its pharmaceutically acceptable salt

where X has the meaning given in claim 3, and at least one pharmaceutically acceptable excipient and/or the media.

5. The use of compounds of General formula (I) or its pharmaceutically acceptable salt for a medicinal product for the treatment of inflammatory disorders

where X represents a-CO-R1or-SO2-R2,
R1represents alkyl (except 5-methylheptane and 6-methylheptane, where the radical R1attached to the carbonyl at position 1), allogeneically, alkoxy (except tert-Butylochka), alkanniny, alkynylaryl or alkylamino radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms), and
R2represents an alkyl radical of 4 to 20 carbon atoms (for example, from 5 to 20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, of 12 to 18 carbon atoms, of 13 to 18 carbon atoms, of 14 to 18 carbon atoms, of 13 to 17 carbon atoms).

6 the Use of compounds of General formula (I') or its pharmaceutically acceptable salt for a medicinal product for the treatment of inflammatory disorders

where X has the meaning given in paragraph 5.

7. The compound according to claim 1, or its pharmaceutically acceptable salt, where alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is linear.

8. The compound according to claim 1, or its pharmaceutically acceptable salt, where alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is branched.

9. The compound according to claim 1, or its pharmaceutically acceptable salt, where alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is either linear or branched, but contains a linear chain of at least 8 or at least 10 carbon atoms.

10. The compound according to claim 1, or its pharmaceutically acceptable salt, where the radical R1has alpha-carbon (position 2 in X), which is substituted by one or two identical or different groups selected from alkyl and halogenating radicals.

11. The connection of claim 10, where the radical R1has alpha-carbon (position 2 in X), which is di-substituted by identical or different groups selected from alkyl and halogenating radicals.

12. The compound of claim 10 or 11, where the alpha carbon is chiral.

13. The connection section 12, where alpha-plastics technology : turning & the d is sp3 hybridized connection.

14. The connection section 12, where the alpha carbon is essentially tetrahedral bond angles.

15. The composition according to claim 3, where the alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is linear.

16. The composition according to claim 3, where the alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is branched.

17. The composition according to claim 3, where the alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is either linear or branched, but contains a linear chain of at least 8 or at least 10 carbon atoms.

18. The composition according to claim 3, where the radical R1has alpha-carbon (position 2 in X), which is substituted by one or two identical or different groups selected from alkyl and halogenating radicals.

19. The composition according to p, where the radical R1has alpha-carbon (position 2 in X), which is di-substituted by identical or different groups selected from alkyl and halogenating radicals.

20. The composition according to p or 19, where the alpha carbon is chiral.

21. The composition according to claim 20, where the alpha carbon is sp3 hybridized connection.

22. The composition according to claim 20, where the alpha carbon is essentially tetrahedral bond angles.

23. The application is about to claim 5, where alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is linear.

24. The use according to claim 5, where the alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is branched.

25. The use according to claim 5, where the alkyl, halogenation, alkoxy, Alchemilla, Alchemilla or alkylamino part of the radical R1is either linear or branched, but contains a linear chain of at least 8 or at least 10 carbon atoms.

26. The use according to claim 5, where the radical R1has alpha-carbon (position 2 in X), which is substituted by one or two identical or different groups selected from alkyl and halogenating radicals.

27. Use p, where the radical R1has alpha-carbon (position 2 in X), which is di-substituted by identical or different groups selected from alkyl and halogenating radicals.

28. Use p or 27, where the alpha carbon is chiral.

29. Use p, where the alpha carbon is sp3 hybridized connection.

30. Use p, where the alpha carbon is essentially tetrahedral bond angles.

31. The compound according to claim 1, which is selected from the group consisting of:
(S)-3-hexadecanaminium;
(S)-3-untechnological is the lactam;
(S)-3-(undec-10-enoyl)aminocaproate;
(S)-3-(undec-10-enoyl)aminocaproate;
(S)-3-dodecanesulfonate;
(S)-3-tetradecanoylphorbol;
(R)-3-hexadecanaminium;
(S)-3-octadecadienoate;
(S)-(Z)-3-(hexadec-9-enoyl)aminocaproate;
(S)-(Z)-3-(octadec-9-enoyl)aminocaproate;
(R)-(Z)-3-(octadec-9-enoyl)aminocaproate;
(S)-3-(2',2'-dimethylcarbamoyl)aminocaproate;
(S)-3-(decyloxybenzoic)aminocaproate;
(S)-(E)-3-(dodec-2-enoyl)aminocaproate;
(S)-3-(Dec-9-ineliminably)aminocaproate;
(S)-3-(decrimination)aminocaproate;
and their pharmaceutically acceptable salts.

32. The pharmaceutical composition according to claim 3 where the compound is selected from the group consisting of:
(S)-3-hexadecanaminium;
(S)-3-andeconomically;
(S)-3-(undec-10-enoyl)aminocaproate;
(S)-3-(undec-10-enoyl)aminocaproate;
(S)-3-dodecanesulfonate;
(S)-3-tetradecanoylphorbol;
(R)-3-hexadecanaminium;
(S)-3-octadecadienoate;
(S)-(Z)-3-(hexadec-9-enoyl)aminocaproate;
(S)-(Z)-3-(octadec-9-enoyl)aminocaproate;
(R)-(Z)-3-(octadec-9-enoyl)aminocaproate;
(S)-3-(2',2'-dimethylcarbamoyl)aminocaproate;
(S)-3-(decyloxybenzoic)aminocaproate;
(S)-(E)-3-(dodec-2-enoyl)aminocaproate is a;
(S)-3-(Dec-9-ineliminably)aminocaproate;
(S)-3-(decrimination)aminocaproate;
and their pharmaceutically acceptable salts.

33. The use according to claim 5, where the compound is selected from the group consisting of:
(S)-3-hexadecanaminium;
(S)-3-andeconomically;
(S)-3-(undec-10-enoyl)aminocaproate;
(S)-3-(undec-10-enoyl)aminocaproate;
(S)-3-dodecanesulfonate;
(S)-3-tetradecanoylphorbol;
(R)-3-hexadecanaminium;
(S)-3-octadecadienoate;
(S)-(Z)-3-(hexadec-9-enoyl)aminocaproate;
(S)-(Z)-3-(octadec-9-enoyl)aminocaproate;
(R)-(Z)-3-(octadec-9-enoyl)aminocaproate;
(S)-3-(2',2'-dimethylcarbamoyl)aminocaproate;
(S)-3-(decyloxybenzoic)aminocaproate;
(S)-(E)-3-(dodec-2-enoyl)aminocaproate;
(S)-3-(Dec-9-ineliminably)aminocaproate;
(S)-3-(decrimination)aminocaproate;
and their pharmaceutically acceptable salts.

34. The compound according to claim 1, which is selected from the group consisting of:
(R)-3-(2',2'-dimethylcarbamoyl)aminocaproate;
(S)-3-(2',2'-dimethylpentane)aminocaproate;
(S)-3-(2',2'-dimethylpent-4-enoyl)aminocaproate;
(S)-3-(2',2'-dimethylpropyl)aminocaproate;
(S)-3-(2',2'-dimethylbutyryl)aminocaproate;
(S,E)-3-(2',2'-dimethylmaleic-4'-enoyl)aminocaproate;
(S)-3-(2',2',5'-trimethylene-4 enoyl)aminocaproate;
(S)-3-(2',2',5'-trimethylhexanoyl)aminocaproate;
(S)-3-(11'-bromoundecanoic)aminocaproate;
(S)-3-(11'-azidoaniline)aminocaproate;
(S)sodium-3-(undecanoyl)aminocaproate-11'-sulfosalicylate;
(S)-3-(decanesulfonate)aminocaproate;
(S)-3-(dodecanesulfonyl)aminocaproate;
(S)-3-(tetradecanoyl)aminocaproate;
(S)-3-(hexadecanesulfonyl)aminocaproate;
(S)-3-(octadecanoyl)aminocaproate;
and their pharmaceutically acceptable salts.

35. The pharmaceutical composition according to claim 3 where the compound is selected from the group consisting of:
(R)-3-(2',2'-dimethylcarbamoyl)aminocaproate;
(S)-3-(2',2'-dimethylpentane)aminocaproate;
(S)-3-(2',2'-dimethylpent-4-enoyl)aminocaproate;
(S)-3-(2',2'-dimethylpropyl)aminocaproate;
(S)-3-(2',2'-dimethylbutyryl)aminocaproate;
(S,E)-3-(2',2'-dimethylmaleic-4'-enoyl)aminocaproate;
(S)-3-(2',2',5'-trimethylene-4'-enoyl)aminocaproate;
(S)-3-(2',2',5'-trimethylhexanoyl)aminocaproate;
(S)-3-(11'-bromoundecanoic)aminocaproate;
(S)-3-(11'-azidoaniline)aminocaproate;
(S)sodium-3-(undecanoyl)aminocaproate-11'-sulfosalicylate;
(S)-3-(decanesulfonate)aminocaproate;
(S)-3-(dodecanesulfonyl)aminocaproate;
(S)-3-(tetradecanoyl)aminocaproate;
(S)-3-(hexadecanesulfonyl)aminocaproate;
(S)-3-(Oct is decanesulfonate)aminocaproate;
and their pharmaceutically acceptable salts.

36. The use according to claim 5, where the compound is selected from the group consisting of:
(R)-3-(2',2'-dimethylcarbamoyl)aminocaproate;
(S)-3-(2',2'-dimethylpentane)aminocaproate;
(S)-3-(2',2'-dimethylpent-4-enoyl)aminocaproate;
(S)-3-(2',2'-dimethylpropyl)aminocaproate;
(S)-3-(2',2'-dimethylbutyryl)aminocaproate;
(S,E)-3-(2',2'-dimethylmaleic-4'-enoyl)aminocaproate;
(S)-3-(2',2',5'-trimethylene-4'-enoyl)aminocaproate;
(S)-3-(2',2',5'-trimethylhexanoyl)aminocaproate;
(S)-3-(11'-bromoundecanoic)aminocaproate;
(S)-3-(11'-azidoaniline)aminocaproate;
(S)sodium-3-(undecanoyl)aminocaproate-11'-sulfosalicylate;
(S)-3-(decanesulfonate)aminocaproate;
(S)-3-(dodecanesulfonyl)aminocaproate;
(S)-3-(tetradecanoyl)aminocaproate;
(S)-3-(hexadecanesulfonyl)aminocaproate;
(S)-3-(octadecanoyl)aminocaproate;
and their pharmaceutically acceptable salts.

37. The compound according to claim 2, which is selected from the group consisting of: (S)-3-hexadecanaminium; (S)-3-(2',2'-dimethylcarbamoyl)aminocaproate; (S)-3-(2',2'-dimethylpropyl)aminocaproate; and
their pharmaceutically acceptable salts.

38. The pharmaceutical composition according to claim 3 where the compound is selected from the group consisting of:
(S)-3-hexadecanaminium; (S)-3-(2',2'-dime illogical)aminocaproate; (S)-3-(2',2'-dimethylpropyl)aminocaproate; and
their pharmaceutically acceptable salts.

39. The use according to claim 5, where the compound is selected from the group consisting of: (S)-3-hexadecanaminium; (S)-3-(2',2'-dimethylcarbamoyl)aminocaproate; (S)-3-(2',2'-dimethylpropyl)aminocaproate; and
their pharmaceutically acceptable salts.

40. The compound according to claim 1, where the compound is selected from the group consisting of:
(S)-3-(2'-propylpentanoic)aminocaproate;
(3S,2'R) and (3S,2'S)-3-(2'-ethylhexanoyl)aminocaproate;
(S)-3-(3',3'-dimethylcarbamoyl)aminocaproate;
(S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate;
(3S,2'R) and (3S,2'S)-3-(2'-methylcatechol)aminocaproate;
(3S,2'S,3'R)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate;
(3S,2'R,3'S)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate;
(3S,3'R) and (3S,3'S)-3-(3'-hydroxy-2',2'-dimethylbutanol)aminocaproate;
(S)-(2',2'-dimethyl-3'-hydroxypropionic)aminocaproate;
(S)-(3'-chloro-2'-(chloromethyl)-2'-methylpropionyl)aminocaproate;
their pharmaceutically acceptable salts.

41. The pharmaceutical composition according to claim 3 where the compound is selected from the group consisting of:
(S)-3-(2'-propylpentanoic)aminocaproate;
(3S,2'R) and (3S,2'S)-3-(2'-ethylhexanoyl)aminocaproate;
(S)-3-(3',3'-dimethylcarbamoyl)aminocaproate;
(S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate;
(3S,2'R) and (3S,2'S)-3-(2'-methylcatechol)is aminocaproate;
(3S,2'S,3'R)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate;
(3S,2'R,3'S)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate;
(3S,3'R) and (3S,3'S)-3-(3'-hydroxy-2',2'-dimethylbutanol)aminocaproate;
(S)-(2',2'-dimethyl-3'-hydroxypropionic)aminocaproate;
(S)-(3'-chloro-2'-(chloromethyl)-2'-methylpropionyl)aminocaproate;
their pharmaceutically acceptable salts.

42. The use according to claim 5, where the compound is selected from the group consisting of:
(S)-3-(2'-propylpentanoic)aminocaproate;
(3S,2'R) and (3S,2'S)-3-(2'-ethylhexanoyl)aminocaproate;
(S)-3-(3',3'-dimethylcarbamoyl)aminocaproate;
(S)-(E)-3-(2'-methyldodec-2'-enoyl)aminocaproate;
(3S,2'R) and (3S,2'S)-3-(2'-methylcatechol)aminocaproate;
(3S,2'S,3'R)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate;
(3S,2'R,3'S)-3-(3'-hydroxy-2'-methyldecyl)aminocaproate;
(3S,3'R) and (3S,3'S)-3-(3'-hydroxy-2',2'-dimethylbutanol)aminocaproate;
(S)-(2',2'-dimethyl-3'-hydroxypropionic)aminocaproate;
(S)-(3'-chloro-2'-(chloromethyl)-2'-methylpropionyl)aminocaproate;
their pharmaceutically acceptable salts.

43. The use according to claim 5 or 6, where the inflammatory disorder is selected from the group consisting of autoimmune diseases, vascular disorders, viral infection or replication, asthma, osteoporosis (low bone mineral density), tumor growth, rheumatoid arthritis, rejection of transplant organs is s and/or delayed graft function or organ, disorders characterized by elevated levels of TNF-α, psoriasis, skin wounds, disorders caused by intracellular parasites, allergies, Alzheimer's disease, is caused by antigen reverse reaction, suppression of the immune response, multiple sclerosis, amyotrophic lateral sclerosis, fibrosis, and formation of adhesions.

44. The method of treatment, mitigation or prevention of the symptoms of inflammatory diseases (including adverse inflammatory reaction to any agent) introduction to the patient an anti-inflammatory amount of a compound according to claim 1 or 2, the composition according to claim 3 or 4, or a medicinal product according to claim 5 or 6.

45. The compound of General formula (I) according to claim 1 or its pharmaceutically acceptable salt, where the substituent R1does not represent a linear alkyl group.

46. The compound of General formula (I) according to claim 1 or its pharmaceutically acceptable salt, where the substituent R1represents a branched alkyl group.

47. The compound according to claim 1 or its pharmaceutically acceptable salt, where the substituent R1not is an alkyl group.

48. The composition according to claim 3, where the substituent R1does not represent a linear alkyl group.

49. The composition according to claim 3, where the substituent R1represents a branched alkyl group.

50. The composition according to claim 3, where the substituent R1not made the focus of an alkyl group.

51. The use according to claim 5, where the substituent R1does not represent a linear alkyl group.

52. The composition according to claim 3, where the substituent R1represents a branched alkyl group.

53. The use according to claim 5, where the substituent R1not is an alkyl group.

54. Synthetic intermediate compound that can be used in the synthesis of compounds of General formula (I) or (I')is selected from the group consisting of:
(E)-methyl-2,2-dimethylmaleic-4-enoate;
(E)-2,2-dimethylmaleic-4-tailhold;
2,2,5-trimethylene-4-tailhold;
3.3 dimethyldodecylamine;
(E)-2-methyldodec-2-tailhold;
(4S,2'S,3'R)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-it;
(4R,2'R,3'S)-4-benzyl-3-(3'-hydroxy-2'-methyldecyl)oxazolidin-2-it;
(2R,3S)-3-hydroxy-2-methyldienolone acid;
2,2-dimethyl-3-(tetrahydropyran-2-yloxy)propionic acid.

55. The compound according to claim 1, which is (S)-3-(1',1'-dimethylaminophenyl)aminocaproate or its pharmaceutically acceptable salt.

56. The pharmaceutical composition according to claim 3 where the compound is an (S)-3-(1',1'-dimethylaminophenyl)aminocaproate or its pharmaceutically acceptable salt.

57. The use according to claim 5, where the compound is an (S)-3-(1',1'-dimethylaminophenyl)aminocaproate or its pharmaceutically acceptable with the eh.



 

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15 cl, 7 tbl, 18 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to technology for preparing caprolactam by the cyclization reaction of derivatives of aminocaproic acid. Method is carried out by cyclizing hydrolysis of compound chosen from the group comprising aminocaproic acid esters or amides, or their mixtures. The process is carried out in the presence of water, in vapor phase at temperature 200-450°C in the presence of a solid catalyst comprising of aluminum oxide that comprises at least one macroporosity with pores volume corresponding to pores with diameter above 500 Å taken in the concentration 5 ml/100 g of above. Preferably, the specific square of catalyst particles is above 10 m2/g and the total volume of pores is 10 ml/100 g or above wherein pores volume corresponds to pores with diameter above 500 Å is 10 ml/100 g or above. Invention provides improving the process indices due to the improved properties of the solid catalyst.

EFFECT: improved preparing method.

5 cl, 2 ex

FIELD: chemistry of lactams' derivatives.

SUBSTANCE: the present innovation deals with obtaining N-(2-chloroalkyl)- and N-alkyl-aromatic derivatives of lactams of the following general formula: , where R=H, Cl, R'=(CH2)3, (CH2)5 which could be modifiers of unsaturated carbon-chain caoutchoucs and rubber mixtures based upon them. The suggested method for obtaining the mentioned N-substituted lactams deals with combining N-chlorolactams and allyl benzene, moreover, as N-lactams one should apply either N-chlorobutyrolactam or N-chlorocaprolactam. The process should be carried out at molar ratio of N-chlorolactam to allyl benzene being equal to 1-1.15:1, at availability of a catalyzer as mono-tertiary-butylperoxy-α-methylmethoxyethoxyethyl ether of ethylene glycol taken at the quantity of 0.4-4.0% weight, in the medium of inert solvent, for example, chlorobenzene at 100-125° C for about 15-20 min. The innovation enables to shorten terms of reaction by 20-30 times, simplify the way for obtaining target products and widen the assortment of the obtained compounds, as well.

EFFECT: higher efficiency.

The invention relates to a method of evaporation aminonitriles and water in the synthesis of lactam by the reaction between aminonitriles and water in the vapor phase in the presence of a catalyst of aluminum hydroxide

The invention relates to the protection of building materials and structures from the biodegradation of microscopic mushrooms

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt

The invention relates to the production of aliphatic lactams from dinitriles
The invention relates to the production of caprolactam, which is used to produce polymeric products

Synthesis of esters // 2227138
The invention relates to an improved method for producing a lower aliphatic esters, including the interaction of lower olefin with a saturated lower aliphatic monocarboxylic acid, preferably in the presence of water in the vapor phase in the presence of heteropolyanions catalyst, characterized in that the reaction is carried out sequentially placed in several reactors or in one long reactor with several successive layers heteropolyanions catalyst and b) initial reagents practically cleared of metallic impurities or compounds of metals so that before coming in contact with heteropolyanions catalyst metals and/or metal compounds is not more than 0.1 ppm

The invention relates to synthetic organic chemistry, namely to a process for the preparation of esters of carboxylic acids of General formula:

< / BR>
where R is alkyl, aryl, substituted aryl, furyl, substituted furyl

R' is alkyl WITH1-C4

The invention relates to catalytic organic chemistry and can find application in the pharmaceutical industry to obtain the drug "Validol", which is a 25-30% solution of menthol in mentilovom broadcast isovalerianic acid (1)
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