RU2365585C2 - Antiinflammatory medications - Google Patents

Abstract

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

Description

The invention relates to the use of 3-aminocaprolactam derivatives for the manufacture of a medicament for the prevention or treatment of inflammatory disorders.

Inflammation is an important component of the physiological defense of the body. However, it is becoming increasingly clear that inflammatory reactions that are undesirable in time and spread play a role in a wide range of diseases, including diseases with an obvious leukocyte component (such as autoimmune diseases, asthma or atherosclerosis), but also for diseases that have not traditionally been considered to be associated with white blood cells ( 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 leukocyte movement in physiological and pathological conditions. With more than 50 ligands and 20 receptors involved in the transmission of chemokine signals, the system has the necessary information density for accessing leukocytes through complex immune regulatory processes from the bone marrow to the periphery, then back through the secondary lymphoid organs. However, this complexity of the chemokine system at first made it difficult to find pharmacological approaches to modulate inflammatory responses by blocking chemokine receptors. It turned out to be difficult to determine which chemokine receptor (s) should be inhibited in order to obtain a therapeutic effect in this inflammatory disease.

совместно называются «Ингибиторами хемокинов широкого спектра» (BSCI). Впоследствии Grainger et al., Biochem. Pharm. 65 (2003) 1027-1034, показали, что BSCI обладают потенциально полезной противовоспалительной активностью для ряда заболеваний на моделях животных. Интересно, что одновременная блокада множества хемокинов не очевидно связана с острой или хронической токсичностью, свидетельствуя о том, что этот подход может представлять собой полезную стратегию для разработки новых противовоспалительных лекарственных средств с преимуществами, подобными стероидам, но со сниженным количеством побочных эффектов.More recently, a family of agents has been described that block signaling simultaneously with a wide range of chemokines (Reckless et al., Biochem J. (1999) 340: 803-811). It was found that the first such agent, a peptide called “peptide 3”, inhibits leukocyte migration induced by 5 different chemokines, while at the same time leaving the migration unchanged in response to other chemoattractants (such as fMLP or TGF-beta). This peptide and its analogues, such as NR58-3.14.3 (i.e., sequence ID No.1

collectively referred to as "Broad Spectrum Chemokine Inhibitors" (BSCI). Subsequently, Grainger et al., Biochem. Pharm. 65 (2003) 1027-1034, showed that BSCIs have potentially useful anti-inflammatory activity for a number of diseases in animal models. Interestingly, concurrent blockade of multiple chemokines is not obviously associated with acute or chronic toxicity, suggesting that this approach may be a useful strategy for developing new anti-inflammatory drugs with benefits similar to steroids, but with fewer side effects.

However, peptides and peptide derivatives, such as NR58-3.14.3, may not be optimal for in vivo use. Their synthesis is quite expensive, and they have relatively unfavorable pharmacokinetic and pharmacodynamic properties. For example, NR58-3.14.3 is not bioavailable when administered orally and, after intravenous injection, is excreted from the blood plasma with a half-life of 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 improved characteristics for their use as pharmaceuticals. First, a number of peptide analogues have been developed, some of which have longer half-lives than NR58-3.14.3, and the synthesis of which is much cheaper. Secondly, a detailed analysis of the structure was carried out: the activity of peptides for the identification of key pharmacophores and the construction of small non-peptide structures that retain the useful properties of the original peptide.

This second approach revealed several structurally different series of compounds that retained the anti-inflammatory properties of peptides, including 16-amino and 16-aminoalkyl derivatives of yohimbine alkaloid, as well as a number of N-substituted 3-aminoglutarimides (Ref: Fox et al., J Med Chem 45 ( 2002) 360-370: WO 99/12968 and WO 00/42071). All of these compounds are broad-spectrum chemokine inhibitors that retain selectivity over non-chemokine chemoattractants, and a number of them have been shown to block acute inflammation in vivo.

The most active and selective of these compounds was (S) -3- (undec-10-enoyl) aminoglutarimide (NR58.4), which inhibited in vitro chemokine-induced migration at an ED _{50 of} 5 nM. However, further studies revealed that the aminoglutarimide ring was susceptible to enzymatic ring opening in serum. Therefore, for some uses (for example, the inflammation being treated is chronic, for example, for autoimmune diseases), these compounds may have non-optimal properties, and a more stable compound with similar anti-inflammatory properties may have advantages.

In order to identify such stable analogues, various derivatives of (S) -3- (undec-10-enoyl) aminoglutarimide were tested for their stability in serum. One such compound, the 6-deoxo analogue of (S) -3- (undec-10-enoyl) tetrahydropyridin-2-one, is completely stable in human serum for at least 7 days at 37 ° C, but has a significantly reduced activity compared to the original molecule.

Amide derivatives of 3-aminocaprolactam have already been disclosed in this field. For example:

- Japanese Patent Application No. 09087331 describes amide derivatives of 3-aminocaprolactam, where the amidalkyl side chain may contain from 2 to 30 carbon atoms. These compounds were presented as oil gelling agents.

- US Pat. No. 6,395,282 describes immunogenic conjugates comprising a carrier molecule coupled to a Gram-negative bacterial autoinducer, wherein said auto-inductor may be an amide derivative of 3-aminocaprolactam, wherein the amidalkyl side chain may contain up to 34 carbon atoms. However, therapeutic use is disclosed only for conjugates , and not for an isolated amide derivative.

- In an article by Weiss et al. (Research Communications in Physiology, Psychiatry and Behavior (1992), 17 (3-4), 153-159) disclosed a number of amide derivatives of 3-aminocaprolactam and among other 3-hexanamido-DL-ε-caprolactam and 3-dodecanamido-DL- ε-caprolactam. These compounds are presented as having only in vitro activity, but without a significant in vivo effect.

In other words, although some alkylamide derivatives of 3-aminocaprolactam have definitely been known in the art, no actual pharmaceutical use has been described for alkylamide derivatives of 3-aminocaprolactam.

The invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an inflammatory disorder:

Where

X represents —CO — R ¹ or —SO ₂ —R ² ,

R ¹ represents an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl or alkylamino radical of 4-20 carbon atoms (e.g., 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 atoms carbon, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms) and

R ² represents an alkyl radical of 4-20 carbon atoms (for example, of 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 atoms carbon, 14-18 carbon atoms, 13-17 carbon atoms).

Alternatively, R ¹ and R ² may be independently selected from a peptide radical containing from 1 to 4 peptide fragments joined by peptide bonds (for example, a peptide radical of 1-4 amino acid residues).

The carbon atom at position 3 of the caprolactam ring is asymmetric, and therefore the compounds of the present invention have two possible enantiomeric forms, that is, the “R” and “S” configurations. The present invention encompasses these two enantiomeric forms and all combinations of these forms, including “RS” racemic mixtures. For the sake of simplicity, when a specific configuration is not shown in the structural formulas, it should be understood that both enantiomeric forms and mixtures thereof are represented.

In the priority applications GB 0327775.3 and 0417436.3 of the same applicant, it is correctly indicated that compounds of the “S” configuration are preferable - in these applications the general formula (I ') demonstrating the “R” configuration is erroneously illustrated.

Preferably, the compounds of general formula (I) or pharmaceutically acceptable salts thereof used in accordance with this aspect of the invention should be compounds of formula (I ')

where X has the same meaning as above.

The carbon atoms in R ¹ and R ² may be linear or branched.

The compounds of general formula (I) or (I ') or their pharmaceutically acceptable salts may be such that the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is either linear or branched, but contains a linear chain of at least 8 or out of at least 10 carbon atoms.

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

Where

X represents —CO — R ¹ or —CO ₂ —R ² ,

R ¹ represents an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl or alkylamino radical of 4-20 carbon atoms (e.g., 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 atoms carbon, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms) and

R ² represents an alkyl radical of 4-20 carbon atoms (for example, of 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 atoms carbon. 14-18 carbon atoms, 13-17 carbon atoms).

Alternatively, R ¹ and R ² may be independently selected from a peptide radical containing from 1 to 4 peptide fragments joined by peptide bonds (for example, a peptide radical of 1-4 amino acid residues).

Preferably, the compound of general formula (I) or a pharmaceutically acceptable salt thereof used in accordance with this aspect of the invention should be compounds of formula (I ')

where X has the same meaning as above.

By pharmaceutically acceptable salt is meant, in particular, salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate, or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate , p-toluenesulfanate, palmoate and stearate. Also within the scope of the present invention, when they can be used, are salts formed from bases, such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

The pharmaceutical composition may be in the form of a solid, for example powders, granules, tablets, gelatine capsules, liposomes or suppositories. Suitable solid bases may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, decrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. Other suitable pharmaceutically acceptable excipients and / or carriers are known to those skilled in the art.

The pharmaceutical compositions of the invention may also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid bases may be, for example, organic solvents such as glycerol or glycols, as well as mixtures thereof in various proportions in water.

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

Where

X represents —CO — R ¹ or —SO ₂ —R ² ,

R ¹ represents an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl or alkylamino radical of 4-20 carbon atoms (e.g., 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 atoms carbon, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms) and

R ² represents an alkyl radical of 4-20 carbon atoms (for example, of 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 atoms carbon, 14-18 carbon atoms, 13-17 carbon atoms).

Alternatively, R ¹ and R ² may be independently selected from a peptide radical containing from 1 to 4 peptide fragments joined by peptide bonds (for example, a peptide radical of 1-4 amino acid residues).

Preferably, the compound of general formula (I) or a pharmaceutically acceptable salt thereof used in accordance with this aspect of the invention should be compounds of formula (I ')

where X has the same meaning as above.

Preferably, the compounds of general formula (I) or (I ') when used in the invention or their salts should be such that the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl or alkylamino part of the radical

R ¹ was either linear or branched, but contained a linear chain of at least 8-10 carbon atoms.

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

- (S) -3-hexadecanoylaminocaprolactam;

- (S) -3-undecanoylaminocaprolactam;

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

- (S) -3- (undec-10-inoyl) aminocaprolactam;

- (S) -3-tetradecanoylaminocaprolactam;

- (R) -3-hexadecanoylaminocaprolactam;

- (S) -3-okstadecanoylaminocaprolactam;

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

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

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

- (S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam;

- (S) -3- (decyloxycarbonyl) aminocaprolactam;

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

- (S) -3- (dec-9-enylaminocarbonyl) aminocaprolactam;

- (S) -3- (decylaminocarbonyl) aminocaprolactam

and their salts.

Most preferred compounds should be selected from the group consisting of:

- (S) -3-hexadecanoylaminocaprolactam (i.e., compounds of formula (I '), where R ¹ is hexadecanyl), - (S) -3- (2', 2'-dimethyldodecanoyl) aminocaprolactam, - (S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam and their salts.

As indicated in the discussion of the prior art, certain alkylamide derivatives of 3-aminocaprolactam may be known as compounds per se (although it is not currently known that any of them have been described as such as pharmaceutical compositions or for medical use in anti-inflammatory context). In the prior art, there may be a description of linear alkylamide derivatives of 3-aminocaprolactam. Although any compound is known per se, this compound is not intended to be a compound claimed per se in this invention, and the applicants disclaim all rights to it. Therefore, the applicant in the present description clearly distinguishes between linear alkyl derivatives covered by the definition of formulas (I) and (I ′) presented here, and branched alkyl derivatives of formulas (I) and (I ′) presented here. ^As used herein, the definition of R ¹ in connection with the compounds themselves may include all alkyl derivatives; alternatively, R ¹ may include all alkyl derivatives, with the exception of certain specified linear alkyl derivatives; alternatively, R ¹ may include all branched alkyl derivatives; and as yet another alternative, the definition of R ¹ may exclude all alkylamide derivatives of 3-aminocaprolactam.

The invention includes certain compounds, compositions and uses thereof, wherein the compound is in hydrated or solvated form.

As indicated in the “Introduction”, certain alkylaminocaprolactam compounds in themselves and compositions / conjugates containing them may already be known in the art. Any such known compounds or compositions should be excluded from the claims of the present invention by excluding a particular or generalized class of compounds / compositions.

The amide derivatives of 3-aminocaprolactam described herein are functional BSCIs. Their synthesis is relatively inexpensive using the easy synthesis pathways provided here; they are stable in human serum and, therefore, have excellent pharmacokinetic properties; they are biologically available when administered orally; they are highly active in vitro broad-spectrum chemokine inhibitors with excellent selectivity compared to non-chemokine chemoattractants; they are highly active and effective in vivo anti-inflammatory drugs in rodent models of inflammation; their administration is not associated with any significant toxicity in the doses necessary to achieve the maximum therapeutic effect. These properties, taken together, indicate that the amide derivatives of 3-aminocaprolactam are anti-inflammatory drugs that have advantages over the previously described compounds.

In comparison with the prior art, an improvement in the present invention consists in the administration of a fragment of aminocaprolactam. However, the chemical structure of the side chain (or alkylamide, alkylsulfonamide or peptide) can also significantly affect the properties of the molecule, so that alkyl substituents with substitution at position 2 (relative to amidecarbonyl) or position 1 (relative to sulfonamide sulfonyl group) are significantly superior to compounds with linear alkyl chains ( or alkylamides or alkylsulfonamides).

The peptides of the prior art (such as NR58-3.14.3) have the disadvantages that: (a) they are expensive and require solid-phase synthesis (at least for longer compounds) and (b) they are very quickly removed through kidneys and (c) they are generally less active.

Prior art aminoglutaramides are cheap, do not excrete rapidly through the kidneys, and are more active, but they do not have metabolic stability.

The improvement described here, aminocaprolactams, are cheap, non-excreted by the kidneys, and even more active, and are also metabolically stable.

In accordance with this invention, inflammatory disorders intended to prevent or treat compounds of the general formula (I) or (I '), or their pharmaceutically acceptable salts, or pharmaceutical compositions or drugs containing them as active ingredients, include, but not limited to :

- autoimmune diseases, for example, such as multiple sclerosis;

- vascular disorders, including stroke, coronary artery disease, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, for example Behcet’s syndrome, giant cell arthritis, polymyalgia rheumatism, Wegener's granulomatosis, Charles Strauss syndrome vasculitis, Genoa Chawaki syndrome and Purpura;

- a viral infection or replication, for example, infection due to viruses or virus replication, including smallpox virus, herpes virus (e.g. Herpesvirus samiri), cytomegalovirus (SMV) or lentivirus;

- asthma;

- osteoporosis (low bone mineral density);

- tumor growth;

- rheumatoid arthritis;

- organ transplant rejection and / or delayed transplant or organ function, for example, in patients with a kidney transplant;

- 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 pulmonary fibrosis);

- the formation of adhesions (in particular, in the abdominal cavity and pelvic region);

- Anamnestic reaction caused by antigen;

- suppression of the immune response.

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

If legally possible, the invention also provides a method of treating, alleviating or preventing the symptoms of inflammatory diseases (including an adverse inflammatory reaction to a substance) by administering to the patient an anti-inflammatory amount of a compound, composition or drug, as claimed herein.

The administration of the drug in accordance with the invention can be carried out by local, oral, parenteral route, intramuscular injection, etc.

The administered dose provided for the medicament in accordance with the invention is from 0.1 mg to 10 g, depending on the type of active compound used.

In accordance with the invention, compounds of general formula (I) or (I ′) can be prepared using the methods described below.

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

All compounds of the general formula (I) or (I ′) can be readily prepared according to general methods known to those skilled in the art.

However, the following preferred synthetic routes are provided:

Chart 1

According to the paths shown in diagram 1:

- 3-aminocaprolactam is treated with an acid chloride of the general formula R ¹ -CO-Cl, where R ¹ is an alkyl, haloalkyl, alkenyl or alkynyl radical, to obtain compounds of the general formula (I), where X is —CO-R ¹ , and R ¹ represents an alkyl, haloalkyl, alkenyl or alkynyl radical; or

- 3-aminocaprolactam is treated with an isocyanate of the general formula R'-NCO, where R 'is alkyl, to give compounds of the general formula (I), where X is —CO-R ¹ and R ¹ is an alkylamino radical;

- 3-aminocaprolactam is treated with a sulfochloride of the general formula R ² —SO ₂ Cl, where R ² is alkyl, to give compounds of the general formula (I), where X is —SO ₂ —R ² and R ² is an alkyl radical; or

- 3-aminocaprolactam is treated with a chloroformate of the general formula R ^'-O-CO-Cl, wherein ^R' is alkyl, to obtain compounds of general formula (I), wherein X represents -CO-R ^1, and R ¹ represents an alkoxy radical .

The reactions shown in diagram 1 can be carried out, for example, in chloroform or dichloromethane. The most preferred reaction solvent is dichloromethane. The above reactions are preferably carried out in the presence of a base, for example Na ₂ CO ₃ .

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

Definitions

The term “about” refers to an interval near the value in question. Used in the present patent application, the term “about X” means an interval from X minus 10% from X to X plus 10% from X, and preferably an interval from X minus 5% from X to X plus 5% from X.

The use of the numerical range in the present description is intended to unambiguously include within the scope of the invention all individual integers within the range and all combinations of the upper and lower limit values within the widest volume of this range. Therefore, for example, the range from 4 to 20 carbon atoms, defined in relation to (among others) the formula I, is intended to include all integers from 4 to 20 and all sub-ranges of each combination of upper and lower values, illustrated definitely or indefinitely.

As used herein, the term “comprising” is to be understood as meaning both “including” and “consisting of”. Therefore, when the invention relates to a “pharmaceutical composition comprising an active ingredient” as a compound, this terminology is intended to encompass both compositions in which other active ingredients may be present, as well as compositions that consist of only one specific active ingredient.

As used herein, the term “peptide fragments” is intended to include the following 20 naturally occurring proteogenic amino acid residues:

Designation VALUE Ala Alanine Cys Cysteine Asp Aspartic acid Glu Glutamic acid Phe Phenylalanine Gly Glycine His Histidine Ile Isoleucine Lys Lysine Leu Leucine Met Methionine Asn Asparagine Pro Proline Gln Glutamine Arg Arginine Ser Serine Thr Threonine Val Valine Trp Tryptophan Tyr Tyrosine

Modified and unusual amino acid residues, as well as peptide mimetics, are also intended to be encompassed by the definition of “peptide fragments”.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by one of ordinary skill in the art to which this invention pertains. Similarly, all publications, patent applications, all patents, and all other references mentioned herein are incorporated by reference (when permitted by law).

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

Blueprints

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

Examples

General procedure for the synthesis of starting compounds

(R) - and (S) -3-aminocaprolactam hydrochlorides and (R, R) - and (S, S) -3-aminocaprolactam hydrochlorides and (S, S) -3-aminocaprolactam were synthesized according to published data (cf. Boyle et al., J Org. Chem., (1979), 44, 4841-4847; Rezler et al., J. Med. Chem. (1997), 40, 3508-3515).

Example 1 : (S) -3-hexadecanoylaminocaprolactam:

(S) -3-aminocaprolactam hydrochloride (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (25 ml) are added to a solution of hexadecanoyl chloride (5 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred in for 2 hours. The organic layer was then separated and the aqueous phase was further extracted with dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (1.41 g; 77%).

Melting point: 99-100 ° C.

(c = 1, CHCl₃) = +32,0.

(c = 1, CHCl ₃ ) = +32.0.

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

¹ H NMR (δ _H , 500 MHz, CDCl ₃ ): 6.88 (1H, d, J 5.5, CHNH), 6.72 (1H, br s, CH ₂ NH), 4.49 (1H , ddd, J 11, 6, 1, CHNH), 3.29-3.16 (2H, m, CH ₂ NH), 2.17 (2H, t, J 7.5, CH ₂ CONH), 2, 03 (1H, broad d, J 13.5, CH ring), 1.98-1.89 (1H, m, CH ring), 1.85-1.73 (2H, m, CH ring), 1 58 (2H, broad kn J 7.0, CH ₂ CH ₂ CONH), 1.43 (1H, broad cd, J 14, 3, CH ring), 1.38-1.29 (1H, broad m, ring CH), 1.29-1.14 (24H, m, (CH ₂ ) ₁₂ ) and 0.83 (3H, t, J 6.5, CH ₃ ).

¹³ C NMR (δ _C , 125 MHz, CDCl ₃ ): 175.9, 172.3 (CO), 52.0 (NHCHCO), 42.1 (NCH ₂ ), 36.6, 31.9, 31, 7, 29.6 (× 6), 29.4, 29.3 (× 2), 29.2, 28.8, 27.9, 25.6, 22.6 (CH ₂ ) and 14.1 ( CH ₃ ).

m / z (C ₂₂ H ₄₂ N ₂ O ₂ Na): 389.31450 (calculated: 389.3144).

Example 2: (S) -3-undecanoylaminocaprolactam :

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of undecanoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred in for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (397 mg; 67%).

Melting point: 91-92 ° C.

(c = 1, CHCl₃) = +30,2.

(c = 1, CHCl ₃ ) = +30.2.

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

¹ H NMR (d _H , 500 MHz, d ₆ -DMSO): 7.76 (1H, t, J 6, CH ₂ N H ), 7.68 (1H, d, J 7, CHN H ), 4, 38 (1H, dd, J 10, 7, C H NH), 3.15 (1H, ddd, J 15.5, 11, 5, C H HNH), 3.04 (1H, dt, J 13, 6 , CH H NH), 2.19-2.06 (2H, m, C H ₂ CONH), 1.85 (1H, dt, J 10.5, 3, C-5 H), 1.77-1 , 68 (2H, m, C-4 H, C-6 H), 1.60 (1H, qt, J 12, 3.5, C-5 H), 1.46 (2H, wide bar J 6 5, C H ₂ CH ₂ CONH), 1.35 (1H, cd, J 12.5, 3, C-4 H), 1.31-1.13 (15H, m, (CH ₂ ) ₇ + C-6 H) and 0.85 (3H, t, J 7.0, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, d _6- DMSO): 174.4 (CO ring), 171.3 (CO chain), 51.3 (NH C HCO), 40.7 (NCH ₂ ) , 35.2, 31.4, 31.3, 29.1, 29.0 (× 2), 28.9, 28.8, 28.7, 27.8, 25.4, 22.2

(CH ₂ ) and 14.0 (CH ₃ ).

m / z (C ₁₇ H ₃₂ N ₂ O ₂ Na): 319.23540 (calculated: 319.2361).

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

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of undec-10-enoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (423 mg; 72%).

Melting point: 83-84 ° C.

(c = 1, CHCl₃) = +40,1.

(c = 1, CHCl ₃ ) = +40.1.

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

¹ H NMR (d _H , 500 MHz, d ₆ -DMSO): 7.75 (1H, t, J 6, CH ₂ N H ), 7.66 (1H, d, J 7, CHN H ), 5, 76 (1H, ddt, J 17, 10, 6.5 CH ₂ = C H ), 4.96 (1H, dd, J 17, 2, C H H = CH), 4.96 (1H, ddt, J 17, 2, 1, C H H = CH), 4.36 (1H, dd, J 10, 7, C H NH), 3.14 (1H, ddd, J 15.5, 11.5, 5, C H HNH), 3.03 (1H, brd, J 13.5.5, CH H NH), 2.16-2.06 (2H, m, C H ₂ CONH), 1.98 (2H , b.k., J 7, CH ₂ = CHC H ₂ ), 1.85 (1H, dt, J 10.5, 3, C-5 H), 1.75-1.67 (2H, m, C -4 H, C-6 H), 1.60 (1H, qt, J 13, 3.5, C-5 H), 1.44 (2H, broad kn., J 7, C H ₂ CH ₂ CONH ), 1.39-1.27 (3H, m, CH ₂ = CHCH ₂ C H ₂ + C-4 H) and 1.31-1,13 (9H, m, (CH ₂ ) ₄ + C-6 H).

¹³ C NMR (d _C , 125 MHz, d _6- DMSO): 174.4 (CO ring), 171.3 (CO chain), 138.9 (CH ₂ = C H), 114.7 ( C H ₂ = CH), 51.3 (NH C HCO), 40.7 (NCH ₂ ), 35.3, 33.3, 31.3, 29.0, 28.9 (× 2) 28.7, 28, 6, 28.4, 27.8 and 25.4 (CH ₂ ).

m / z (C ₁₇ H ₃₀ N ₂ O ₂ Na): 317.21970 (calculated: 317.2205).

Example 4: (S) -3- (undec-10-inoyl) aminocaprolactam :

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of undec-10-inoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (362 mg; 62%).

Melting point: 73-75 ° C.

(c = 1, CHCl₃) = +42,1.

(c = 1, CHCl ₃ ) = +42.1.

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

¹ H NMR (d _H , 500 MHz, d _6- DMSO): 7.76 (1H, t, J 5.5, CH ₂ N H ), 7.68 (1H, d, J 7, CHN H ), 4.36 (1H, dd, J 11, 7, C H NH), 3.16 (1H, ddd, J 15.5, 11.5, 5, C H HNH), 3.03 (1H, broad. dt, J 14, 7, CH H NH), 2.17-2.07 (4H, m, C H ₂ CONH + C H ₂ CCH), 1.85 (1H, m, C-5 H), 1 , 77-1.67 (2H, m, C-4 H, C-6 H), 1.62 (1H, br.kt, J 13, 3.0, C-5 H), 1.50-1 , 28 (5H, m, C H ₂ CH ₂ CONH +

HCCCH ₂ C H ₂ + C-4 H) and 1.28-1.13 (9H, m, (CH ₂ ) ₄ + C-6 H).

¹³ C NMR (d _C , 125 MHz, d ₆ -DMSO): 174.4 (CO ring), 171.3 (CO chain), 84.6 (CH ₂ C CH), 71.1 (CH ₂ C C H), 51.3 (NH C HCO), 40.7 (NCH ₂ ), 35.2, 31.3, 29.0, 28.8, 28.7, 28.5, 28.2, 28.0, 27.8, 25.4 and 17.8 (CH ₂ ).

m / z (C ₁₇ H ₂₈ N ₂ O ₂ Na): 317.20470 (calculated: 315.2048).

Example 5: (S) -3-dodecanoylaminocaprolactam :

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of dodecanoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred in for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (439 mg; 71%).

Melting point: 93-94 ° C.

(c = 1, CHCl₃) = +35,5.

(c = 1, CHCl ₃ ) = +35.5.

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

¹ H NMR (d _H , 500 MHz, d _6- DMSO): 7.76 (1H, br s, CH ₂ N H ), 7.67 (1H, d, J 7, CHN H ), 4.38 (1H, dd, J 10.5, 7.5, C H NH), 3.15 (1H, ddd, J 15.5, 11.5, 5, C H HNH), 3.05 (1H, dt , J 14.5, 5.5, CH H NH), 2.17-2.07 (2H, m, C H ₂ CONH), 1.90-1.80 (1H, m, C-5 H) 1.77-1.68 (2H, m, C-4 H, C-6 H), 1.62 (1H, br.kt, J 12, 3.5, C-5 H), 1.46 (2H, broad kn. J 6.0, C H ₂ CH ₂ CONH), 1.36 (1H, cd, J 12.5, 2.5, C-4 H), 1.31-1.13 ( 17H, m, (CH ₂ ) ₈ + C-6 H) and 0.85 (3H, t, J 6.5, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, d ₆ -DMSO): 174.4 (CO ring), 171.2 (CO chain), 51.3 (NH C HCO), 40.7 (NCH ₂ ) , 35.3, 31.4, 31.3, 29.1 (× 3), 29.0 (× 2), 28.8, 28.7, 27.8, 25.4, 22.2

(CH ₂ ) and 14.0 (CH ₃ ).

m / z (C ₁₈ H ₃₄ N ₂ O ₂ Na): 333.25-150 (calculated: 333.2518).

Example 6: (S) -3-tetradecanoylaminocaprolactam :

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of tetradecanoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred in for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (412 mg; 61%).

Melting point: 97-98 ° C.

(c = 1, CHCl₃) = +33,2.

(c = 1, CHCl ₃ ) = +33.2.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.87 (1H, d, J 5.5, CHN H ), 6.66-6.48 (1H, broad m, CH ₂ N H ) 4.50 (1H, dd, J 11.6, C H NH), 3.30-3.16 (2H, m, C H ₂ NH), 2.18 (2H, t, J 7.5, C H ₂ CONH), 2.04 (1H, broad d, J 13.5, CH ring), 2.00-1.92 (1H, m, CH ring), 1.86-1.74 (2H m, CH ring), 1.59 (2H, broad kn. J 7.0, C H ₂ CH ₂ CONH), 1.43 (1H, broad kn., J 12.5, CH ring), 1, 31 (1H, brq, J 13, CH ring), 1.31-1.13 (20H, m, (CH ₂ ) ₁₀ ) and 0.85 (3H, t, J 6.5, CH ₃ ) .

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 175.9, 172.3 (CO), 52.0 (NH C HCO), 42.1 (NCH ₂ ), 36.6, 31.9, 31.7, 29.6 (× 4), 29.4, 29.3 (× 2), 29.2, 28.8, 27.9, 25.6, 22.6 (CH ₂ ) and 14, 1 (CH ₃ ).

m / z (C ₂₀ H ₃₈ N ₂ O ₂ Na): 361.28270 (calculated: 361.2831).

Example 7: (R) -3-hexadecanoylaminocaprolactam :

Hydropyrrolidine-5-carboxylate (R, R) -3-aminocaprolactam (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (25 ml) are added to a solution of hexadecanoyl chloride (5 mmol) in dichloromethane (25 ml) at ambient temperature medium and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (1.23 g; 67%).

Melting point: 99-100 ° C.

(c = 1, CHCl₃) = -32,0.

(c = 1, CHCl ₃ ) = -32.0.

Example 8: (S) -3-octadecanoylaminocaprolactam :

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of octadecanoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture is stirred in for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give the title compound (648 mg; 82%).

Melting point: 87-88 ° C.

(c = 1, CHCl₃) = +31,9.

(c = 1, CHCl ₃ ) = +31.9.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.88 (1H, d, J 5.5, CHN H ), 6.72-6.58 (1H, broad m, CH ₂ N H ) 4.50 (1H, dd, J 11.6, C H NH), 3.29-3.16 (2H, m, C H ₂ NH), 2.17 (2H, t, J 7.5, C H ₂ CONH), 2.03 (1H, brd, J 13, CH ring), 1.99-1.90 (1H, m, CH ring), 1.86-1.73 (2H, m , CH ring), 1.58 (2H, br. J 7.0, C H ₂ CH ₂ CONH), 1.42 (1H, br. J, 14, 3, CH), 1.38- 1.30 (1H, broad m, CH ring), 1.30-1.14 (28H, m, (CH ₂ ) ₁₄ ) and 0.84 (3H, t, J 6.5, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 175.9, 172.3 (CO), 52.0 (NH C HCO), 42.1 (NCH ₂ ), 36.6, 31.9, 31.7, 29.6 (× 8), 29.4, 29.3 (× 2), 29.2, 28.8, 27.9, 25.6, 22.6 (CH ₂ ) and 14, 1 (CH ₃ ).

m / z (C ₂₄ H ₄₆ N ₂ O ₂ Na): 417.34460 (calculated: 417.3457).

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

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of (Z) -hexa-9-enoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (406 mg; 56%).

Melting point: 67-68 ° C.

(c = 1, CHCl₃) = +33,2.

(c = 1, CHCl ₃ ) = +33.2.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.88 (1H, d, J 5.5, CHN H ), 6.67 (1H, br s, CH ₂ N H ), 5.33 -5.25 (2H, m, C H = C H ), 4.50 (1H, ddd, J 11, 6, 1, C H NH), 3.29-3.16 (2H, m, C H ₂ NH), 2.17 (2H, t, J 7.5, C H ₂ CONH), 2.03 (1H, broad d, J 13, CH ring), 1.99-1.90 (5H, m, ring CH + C H ₂ CH = CHC H ₂ ), 1.84-1.72 (2H, m, ring CH), 1.58 (2H, br. J 7.0, C H ₂ CH ₂ CONH), 1.43 (1H, broad cd, J 14, 3, CH ring), 1.38-1.30 (1H, wide m, CH ring), 1.30-1.14 (16H, m, (C H ₂ ) ₄ CH ₂ CH = CHCH ₂ (C H ₂ ) ₄ ) and 0.84 (3H, t, J 7, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 175.9, 172.3 (CO), 129.8 (× 2) (CH = CH), 52.0 (NH C HCO), 42.0 (NCH ₂ ), 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 (CH ₂ ) and 14.1 (CH ₃ ).

m / z (C ₂₂ H ₄₀ N ₂ O ₂ Na): 387.29700 (calculated: 387.2987).

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

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of (Z)-octadec-9-enoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (514 mg; 66%).

Melting point: 66-67 ° C.

(c = 1, CHCl₃) = +30,9.

(c = 1, CHCl ₃ ) = +30.9.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.88 (1H, d, J 5.5, CHN H ), 6.74 (1H, br t, J 5, CH ₂ N H ), 5.33-5.24 (2H, m, C H = C H ), 4.49 (1H, ddd, J 11.6, 1.5, C H NH), 3.29-3.14 (2H m, C H ₂ NH), 2.16 (2H, t, J 7.5, C H ₂ CONH), 2.03 (1H, broad d, J 13.5, CH ring), 1.99 -1.89 (5H, m, ring CH + C H ₂ CH = CHC H ₂ ), 1.84-1.72 (2H, m, ring CH), 1.58 (2H, br. J 7, 0, C H ₂ CH ₂ CONH), 1.42 (1H, broad cd, J 14, 3, CH ring), 1.38-1.30 (1H, wide m, CH ring), 1.30 -1.14 (20H, m, (C H ₂ ) ₆ CH ₂ CH = CHCH ₂ (C H ₂ ) ₄ ) and 0.83 (3H, t, J 7, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 175.9, 172.3 (CO), 129.9, 129.7 (CH = CH), 52.0 (NH C HCO), 42.0 (NCH ₂ ), 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 (CH ₂ ) and 14.1 (CH ₃ ).

m / z (C ₂₄ H ₄₄ N ₂ O ₂ Na): 415.32820 (calculated: 415.3300).

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

Hydropyrrolidine-5-carboxylate (R, R) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of (Z)-octadec-9-enoyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (574 mg; 73%).

Melting point: 66-67 ° C.

(c = 1, CHCl₃) = -31,4.

(c = 1, CHCl ₃ ) = -31.4.

Example 12: (S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam :

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of 2,2-dimethyldodecanoyl chloride (2 mmol) in dichloromethane (25 ml ) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (543 mg; 80%).

Melting point: 41-42 ° C.

(c = 1, CHCl₃) = +28,0.

(c = 1, CHCl ₃ ) = +28.0.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 7.08 (1H, d, J 5.5, CHN H ), 6.67 (1H, br s, CH ₂ N H ), 4.44 (1H, dd, J 11.5.5, C H NH), 3.28-3.15 (2H, m, C H ₂ NH), 2.01 (1H, broad d, J 13, CH ring ), 1.98-1.89 (1H, m, CH ring), 1.84-1.72 (2H, m, CH ring), 1.47-1.30 (3H, m, CH ring) + C H ₂ CMe ₂ CONH), 1.27-1.15 (17H, broad m, ring CH + (CH ₂ ) ₈ ) 1.13 (3H, s, CM e Me), 1.12 (3H , s, CMe Me ) and 0.82 (3H, t, J 7, CH ₂ C H ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 177.1, 176.0 (CO), 52.0 (NH C HCO), 41.9 ( CM e ₂ ), 42.1, 41.3 , 31.8, 31.5, 30.1, 29.6, 29.5 (× 2), 29.3, 28.9, 27.9 (CH ₂ ), 25.3, 25.2 (CH ₃ ), 24.8, 22.6 (CH ₂ ) and 14.1 (CH ₃ ).

m / z (C ₂₀ H ₃₈ N ₂ O ₂ Na): 361.28350 (calculated: 361.2831).

(c = 1, CHCl₃) +28,0;

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

(c = 1, CHCl ₃ ) +28.0;

(c = 0.87, MeOH) +13.3.

Example 13: (S) -3- (decyloxycarbonyl) aminocaprolactam :

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of decyl chloroformate (2 mmol) in dichloromethane (25 ml) at ambient temperature medium and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (469 mg; 74%).

Melting point: 40-41 ° C.

(c = 1, CHCl₃) = +31,4.

(c = 1, CHCl ₃ ) = +31.4.

IR: n _max (cm ^-1 ): 3352, 3300 (NH), 1682, 1657, 1637 (CO), 1513 (NH).

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.86 (1H, br s, CH ₂ N H ), 6.72 (1H, d, J 6 CHN H ), 4.49 (1H, dd, J 11.6, C H NH), 3.99 (2H, t, J 6, OCH ₂ ), 3.26-3.14 (2H, m, C H ₂ NH), 2.04 (1H broad d, J 13.5, CH ring), 2.00-1.91 (1H, m, CH ring), 1.82-1.68 (2H, m, CH ring), 1.55 ( 2H, broad kn. J 7.0, C H ₂ CH ₂ O), 1.48 (1H, broad cd, J 14, 2.5, ring CH), 1.38-1.31 (1H, broad m, ring CH), 1.29-1.17 (14H, m, (CH ₂ ) ₇ ) and 0.83 (3H, t, J 7, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 175.8, 155.9 (CO), 65.0 (OCH ₂ ), 53.5 (NH C HCO), 42.0 (NCH ₂ ), 32.1, 31.8, 29.5 (× 2), 29.2 (× 2), 29.0, 28.8, 28.0, 25.8, 22.6 (CH ₂ ) and 14, 1 (CH ₃ ).

m / z (C ₁₇ H ₃₂ N ₂ O ₃ Na): 335.23190 (calculated: 335.2311).

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

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of dodec-2-enoyl chloride (2 mmol) in dichloromethane (25 ml ) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (472 mg; 77%).

Melting point: 87-88 ° C.

(c = 1, CHCl₃) = +44,7.

(c = 1, CHCl ₃ ) = +44.7.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.94 (1H, d, J 5.5, CHN H ), 6.84 (1H, br s, CH ₂ N H ), 6.78 (1H, dt, J 15.5, 7, CH ₂ C H = CH), 5.80 (1H, d, J 15.5, CH ₂ CH = C H ), 4.56 (1H, ddd, J 11, 6, 1.5, C H NH), 3.29-3.15 (2H, m, C H ₂ NH), 2.11 (2H, q, J 7, C H ₂ CH = CH), 2.07 (1H, brd, J 13.5, CH ring), 1.98-1.90 (1H, m, CH ring), 1.86-1.73 (2H, m, CH ring) 1.44 (1H, broad cd, J 14, 2.5, CH ring), 1.41-1.29 (3H, wide m, CH + C H ₂ CH ₂ CH ₂ CH = CH), 1 29-1.14 (12H, m, (CH ₂ ) ₆ ) and 0.82 (3H, t, J 6.5, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 175.9, 165.0 (CO), 144.8, 123.5 (CH = CH), 52.0 (NH C HCO), 42.0 (NCH ₂ ), 32.0, 31.8, 31.6, 29.4 (× 2), 29.2, 29.1, 28.8, 28.2, 27.9, 22.6 (CH ₂ ) and 14.1 (CH ₃ ).

m / z (C ₁₈ H ₃₂ N ₂ O ₂ Na): 331.23570 (calculated: 331.2361).

Example 15: (S) -3- (dec-9-enylaminocarbonyl) aminocaprolactam :

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of dec-9-enylisocyanate (2 mmol) in dichloromethane (25 ml ) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (347 mg; 56%).

Melting point: 98-99 ° C.

(c = 1, CHCl₃) = +27,3.

(c = 1, CHCl ₃ ) = +27.3.

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

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.64 (1H, br s, CH ₂ N H ring), 6.12 (1H, d, J 6 CHN H ), 5.75 (1H , dddd, J 17, 10, 6.5, 1.5, CH ₂ = C H ), 5.21-5.12 (1H, br m, urea CH ₂ NH), 4.93 (1H, dc , J 17, 1.5, C H H = CH), 4.87 (1H, broad d, J 10, CH H = CH), 4.49 (1H, dd, J 11, 6, NHC H CO ), 3.25 (1H, ddd, J 15.5, 12, 4, ring CH ₂ N), 3.17 (1H, dt, J 14, 6, ring CH ₂ N), 3.11-3, 02 (2H, m, urea NHC H ₂ ), 2.05-1.87 (4H, broad m, ring CH × 2 + C H ₂ CH = CH), 1.82-1.70 (2H, m ring CH), 1.48-1.36 (3H, br m, chain C H ₂ CH ₂ NH, + ring CH), 1.36-1.27 (3H, m, ring CH + chain CH ₂ ) and 1.27-1.17 (8H, m, chain (CH ₂ ) ₄ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 177.2, 157.6 (CO), 139.1, 114.1 (CH = CH), 52.7 (NH C HCO), 42.1 , 40.3 (NCH ₂ ), 33.7, 32.9, 30.3, 29.4, 29.3, 29.0, 28.8 (× 2), 27.9 and 26.9 (CH ₂ ).

m / z (C ₁₇ H ₃₁ N ₃ O ₂ Na): 332.23150 (calculated: 332.2314).

Example 16: (S) -3- (decylaminocarbonyl) aminocaprolactam :

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of decylisocyanate (2 mmol) in dichloromethane (25 ml) at ambient temperature medium and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: EtOAc to 9: 1 EtOAc: MeOH) to obtain the title compound (401 mg; 64%).

Melting point: 97-98 ° C.

(c = 1, CHCl₃) = +27,7.

(c = 1, CHCl ₃ ) = +27.7.

IR: n _max (cm ^-1 ): 3359, 3316 (NH), 1621, (CO), 1558 (NH).

¹ H NMR (d _H , 500 MHz, CDCl ₃ ): 6.62 (1H, br s, CH ₂ N H ring), 6.09 (1H, d, J 6 CHN H ), 5.16 (1H , br t, J 5, urea CH ₂ NH), 4.48 (1H, ddd, J 11, 6, 1, NHC H CO), 3.26 (1H, ddd, J 16, 11, 5, ring CH ₂ N), 3.17 (1H, dt, J 15, 7, ring CH ₂ N), 3.11-3.02 (2H, m, urea NHC H ₂ ), 2.02 (1H, broad. d J 14, CH ring), 1.96-1.87 (1H, m, CH ring), 1.83-1.70 (2H, m, CH ring), 1.48-1.27 (4H, m, ring CH × 2 + chain CH ₂ ), 1.27-1.14 (14H, m, (CH ₂ ) ₇ ) and 0.82 (3H, t, J 7, CH ₃ ).

¹³ C NMR (d _C , 125 MHz, CDCl ₃ ): 177.2, 157.6 (CO), 52.7 (NH C HCO), 42.1, 40.4 (NCH ₂ ), 32.9, 31.8, 30.2, 29.6, 29.5, 29.4, 29.3, 28.8, 27.9, 26.9, 22.6 (CH ₂ ) and 14.1.

m / z (C ₁₇ H ₃₃ N ₃ O ₂ Na): 334.24880 (calculated: 334.2470).

Example 17: (R) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam :

(c = 1, CHCl₃) -25,7;

(c = 0,5, МeOH) -12,2.Hydropyrrolidine-5-carboxylate (R, R) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of 2,2-dimethyldodecanoyl chloride (2 mmol) in dichloromethane (25 ml ) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc: 1: 3 hexane to EtOAc) to obtain (R) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam (515 mg; 76%); melting point: 48-49 ° C;

(c = 1, CHCl ₃ ) -25.7;

(c = 0.5, MeOH) -12.2.

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

Example 18: (S) -3- (2 ', 2'-dimethylpentanoyl) aminocaprolactam:

(c = 1, CHCl₃) +30,7; n_max/см^-1 3387, 3239 (NH), 1655, 1634 (CO), 1507 (NH);Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (20 mmol) and Na ₂ CO ₃ (60 mmol) in water (50 ml) are added to a solution of 2,2-dimethylpentanoyl chloride (20 mmol) in dichloromethane (50 ml ) at ambient temperature and the reaction mixture was stirred for 12 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was recrystallized from EtOAc / hexane to give (S) -3- (2 ', 2'-dimethylpentanoyl) aminocaprolactam (3.50 g; 77%); melting point: 84-85 ° C;

(c = 1, CHCl ₃ ) +30.7; n _max / cm ^-1 3387, 3239 (NH), 1655, 1634 (CO), 1507 (NH);

d _H (500 MHz, CDCl ₃ ) 7.08 (1H, d, J 5, CHN H ), 6.53 (1H, br s, CH ₂ N H ), 4.45 (1H, ddd, J 11 5.5, 1.5, C H NH), 3.29-3.16 (2H, m, C H ₂ NH), 2.00 (1H, broad d, J 13, CH ring), 1 98-1.92 (1H, m, CH ring), 1.84-1.73 (2H, m, CH ring), 1.47-1.30 (4H, wide m, CH × 2 + ring) C H ₂ CMe ₂ CONH), 1.23-1.15 (2H, m, C H ₂ CH ₃ ) 1.14 (3H, s, CM e Me), 1.13 (3H, s, CMe Me ) and 0.84 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 177.0, 176.1 (CO), 52.1 (NH C HCO), 43.6, 42.0 (× 2, one of which is CM e ₂ ), 31.5, 28.9, 27.9 (CH ₂ ), 25.3, 25.2 (CH ₃ ), 18.0 (CH ₂ ) and 14.5 (CH ₃ ); m / z (M ⁺ C ₁₃ H ₂₄ N ₂ O ₂ requires 240.18378) 240.18437.

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

(c = 1, CHCl₃) +27,7; n_max/см^-1 3395, 3304 (NH), 1675, 1633 (CO), 1534 (NH); d_H (500 МГц, CDCl₃) 7,10 (1H, д, J 4,5, CHNH), 6,48 (1H, шир.с, CH₂NH), 5,68 (1H, ддт, J 17, 10, 7,5, CH=CH₂), 5,02 (1H, шир.д, J 17 CH=CHH), 5,00 (1H, шир.д, J 10, CH=CHH), 4,45 (1H, дд, J 11, 5,5, CHNH), 3,30-3,17 (2H, м, CH ₂NH), 2,27 (1H, J 14, 7,5, CHHCH=CH₂), 2,22 (1H, дд, J 14, 7,5, CHHCH=CH₂), 2,01 (1H, шир.д, J 13, кольцо CH), 1,98-1,92 (1H, м, кольцо CH), 1,85-1,73 (2H, м, кольцо CH), 1,47-1,30 (2H, шир.м, кольцо CH ×2), 1,16 (3H, с, СМeМe) и 1,15 (3H, с, СМeМe); d_C (125 МГц, CDCl₃) 176,4, 175,9 (CO), 134,2 (CH=CH₂), 117,8 (CH=CH₂), 52,1 (NHCHCO), 45,2, 42,1 (CH₂), 41,9 (СМe₂), 31,5, 28,9, 27,9 (CH₂), 25,0 и 24,9 (CH₃); m/z (М⁺ C₁₃H₂₂N₂O₂ требует 238,16813) 238,16834.Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (20 mmol) and Na ₂ CO ₃ (60 mmol) in water (50 ml) are added to a solution of 2,2-dimethylpent-4-enoyl chloride (20 mmol) in dichloromethane (50 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (1: 1 EtOAc: hexane to EtOAc) to obtain (S) -3- (2 ', 2'-dimethylpent-4-enoyl) aminocaprolactam (1.43 g; 32%); melting point: 71-72 ° C;

(c = 1, CHCl ₃ ) +27.7; n _max / cm ^-1 3395, 3304 (NH), 1675, 1633 (CO), 1534 (NH); d _H (500 MHz, CDCl ₃ ) 7.10 (1H, d, J 4.5, CHN H ), 6.48 (1H, br s, CH ₂ N H ), 5.68 (1H, ddt, J 17, 10, 7.5, C H = CH ₂ ), 5.02 (1H, broad d, J 17 CH = C H H), 5.00 (1H, wide d, J 10, CH = CH H ), 4.45 (1H, dd, J 11.5.5, C H NH), 3.30-3.17 (2H, m, C H ₂ NH), 2.27 (1H, J 14 7.5, C H HCH = CH ₂ ), 2.22 (1H, dd, J 14, 7.5, CH H CH = CH ₂ ), 2.01 (1H, broad d, J 13, ring CH), 1.98-1.92 (1H, m, CH ring), 1.85-1.73 (2H, m, CH ring), 1.47-1.30 (2H, m wide, ring CH × 2), 1,16 (3H, s, e CM ME) and 1,15 (3H, s, SMe ME); d _C (125 MHz, CDCl ₃ ) 176.4, 175.9 (CO), 134.2 ( C H = CH ₂ ), 117.8 (CH = C H ₂ ), 52.1 (NH C HCO) 45.2, 42.1 (CH ₂ ), 41.9 ( CM e ₂ ), 31.5, 28.9, 27.9 (CH ₂ ), 25.0 and 24.9 (CH ₃ ); m / z (M ⁺ C ₁₃ H ₂₂ N ₂ O ₂ requires 238.16813) 238.16834.

Example 20: (S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam :

(c = 1, CHCl₃) +39,5; n_max/см^-1 3381, 3255 (NH), 1680, 1632 (CO), 1506 (NH); d_H (500 МГц, CDCl₃) 7,10 (1H, д, J 5,0, CHNH), 6,75 (1H, шир.с, CH₂NH), 4,42 (1H, ддд, J 11, 5,5, 1,5, CHNH), 3,27-3,16 (2H, м, CH ₂NH), 2,03-1,89 (2H, м, 2 × кольцо CH), 1,83-1,71 (2H, м, 2 × кольцо CH), 1,45-1,28 (2H, м, 2 × кольцо CH) и 1,15 (9H, с, 3 × CH₃); d_C (125 МГц, CDCl₃) 177,7, 176,1 (CO), 52,1 (NHCHCO), 42,0 (CH₂N), 40,5 (CCO), 31,5, 28,9, 27,9 (CH₂ лактaм), 27,4 (3 × CH₃).Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (15 ml) are added to a solution of 2,2-dimethylpropionyl chloride (5 mmol) in dichloromethane (15 ml ) at ambient temperature and the reaction mixture was stirred for 12 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was recrystallized from EtOAc / hexane to give (S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam (645 mg; 61%); melting point: 126-127 ° C;

(c = 1, CHCl ₃ ) +39.5; n _max / cm ^-1 3381, 3255 (NH), 1680, 1632 (CO), 1506 (NH); d _H (500 MHz, CDCl ₃ ) 7.10 (1H, d, J 5.0, CHN H ), 6.75 (1H, broad s, CH ₂ N H ), 4.42 (1H, ddd, J 11, 5.5, 1.5, C H NH), 3.27-3.16 (2H, m, C H ₂ NH), 2.03-1.89 (2H, m, 2 × CH ring ), 1.83-1.71 (2H, m, 2 × CH ring), 1.45-1.28 (2H, m, 2 × CH ring) and 1.15 (9H, s, 3 × CH ₃ ); d _C (125 MHz, CDCl ₃ ) 177.7, 176.1 (CO), 52.1 (NH C HCO), 42.0 (CH ₂ N), 40.5 ( C CO), 31.5, 28.9, 27.9 (CH ₂ lactams), 27.4 (3 × CH ₃ ).

m / z (MNa ⁺ C ₁₁ H ₂₀ N ₂ O ₂ Na requires 235.141699) 235.142237; (MH ⁺ C ₁₁ H ₂₁ N ₂ O ₂ requires 213.1597543) 213.160246.

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

(c = 1, CHCl₃) +33,6; n_max/см^-1 3400, 3278 (NH), 1677, 1630 (CO), 1500 (NH); d_H (500 МГц, CDCl₃) 7,08 (1H, д, J 5,0, CHNH), 6,72 (1H, шир.с, CH₂NH), 4,44 (1H, ддд, J 11, 5,5, 1,5, CHNH), 3,28-3,16 (2H, м, CH ₂NH), 2,04-1,90 (2H, м, 2 × кольцо CH), 1,83-1,72 (2H, м, 2 × кольцо CH), 1,57-1,44 (2H, м, CH₂CH₃), 1,44-1,30 (2H, м, 2 × кольцо CH) 1,12 (3H, с, CH₃) 1,11 (3H, с, CH₃) и 0,78 (3H, т, J 7,5, CH ₂CH₃); d_C (125 МГц, CDCl₃) 177,0, 176,0 (CO), 52,1 (NHCHCO), 42,2 (CCO), 42,0 (CH₂N), 33,7 (CH₂CH₃), 31,6, 28,9, 27,9 (CH₂ лактaм), 24,8, 24,7 (CCH₃) и 9,1 (CH₂ CH₃); m/z (МH⁺ C₁₂H₂₃N₂O₂ требует 227,1760) 227,1767.Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (15 ml) are added to a solution of 2,2-dimethylbutyryl chloride (5 mmol) in dichloromethane (15 ml ) at ambient temperature and the reaction mixture was stirred for 12 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was recrystallized from EtOAc / hexane to give (S) -3- (2 ', 2'-dimethylbutyryl) aminocaprolactam (562 mg; 50%); melting point: 106-107 ° C;

(c = 1, CHCl ₃ ) +33.6; n _max / cm ^-1 3400, 3278 (NH), 1677, 1630 (CO), 1500 (NH); d _H (500 MHz, CDCl ₃ ) 7.08 (1H, d, J 5.0, CHN H ), 6.72 (1H, broad s, CH ₂ N H ), 4.44 (1H, ddd, J 11, 5.5, 1.5, C H NH), 3.28-3.16 (2H, m, C H ₂ NH), 2.04-1.90 (2H, m, 2 × CH ring ), 1.83-1.72 (2H, m, 2 × CH ring), 1.57-1.44 (2H, m, CH ₂ CH ₃ ), 1.44-1.30 (2H, m, 2 × ring CH) 1.12 (3H, s, CH ₃ ) 1.11 (3H, s, CH ₃ ) and 0.78 (3H, t, J 7.5, C H ₂ CH ₃ ); d _C (125 MHz, CDCl ₃ ) 177.0, 176.0 (CO), 52.1 (NH C HCO), 42.2 ( C CO), 42.0 (CH ₂ N), 33.7 ( C H ₂ CH ₃ ), 31.6, 28.9, 27.9 (CH ₂ lactams), 24.8, 24.7 (C C H ₃ ) and 9.1 (CH ₂ C H ₃ ); m / z (MH ⁺ C ₁₂ H ₂₃ N ₂ O ₂ requires 227.1760) 227.1767.

Example 22: (S, E) -3- (2 ', 2'-dimethyldodec-4'-enoyl) aminocaprolactam :

(c = 1, CHCl₃) +21,6; n_max/см^-1 3264 (NH), 1639 (CO), 1497 (NH); d_H (500 МГц, CDCl₃) 7,09 (1H, д, J 5,5, CHNH), 6,67-6,32 (1H, шир.м, CH₂NH), 5,42 (1H, дт, J 15, 6,5, CH=CH), 5,28 (1H, дт, J 15, 7, CH=CH), 4,44 (1H, дд, J 11, 5,5, CHNH), 3,30-3,17 (2H, м, CH ₂NH), 2,20 (1H, дд, 13,5, 7, CH=CHCH ₂), 2,14 (1H, дд, 13,5, 7, CH=CHCH ₂), 2,01-1,87 (4H, шир.м, кольцо CH ×2, + CH ₂CH=CH), 1,87-1,74 (2H, м, кольцо CH), 1,47-1,32 (2H, м, кольцо CH), 1,27-1,15 (10H, шир.м, (CH₂)₅) 1,13 (3H, с, СМeМe), 1,12 (3H, с, СМeМe) и 0,83 (3H, т, J 7, CH₂CH ₃); d_C (125 МГц, CDCl₃) 176,8, 176,0 (CO), 134,2, 125,2 (CH=CH), 52,1 (NHCHCO), 43,9 (CH₂), 42,1 (×2) (CH₂ + СМe₂), 32,6, 31,8, 31,5, 30,1, 29,4, 29,1 (×2), 28,9, 27,9 (CH₂), 25,0, 24,8 (CH₃) и 22,6 (CH₃); m/z (МH⁺ C₂₀H₃₇N₂O₂ требует 337,2855) 337,2858.Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (10 mmol) and Na ₂ CO ₃ (30 mmol) in water (30 ml) are added to a solution of 2,2-dimethyldodec-2-enoyl chloride (crude, resulting the above reaction) (10 mmol) in dichloromethane (30 ml) at ambient temperature and the reaction mixture was stirred for 12 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (1: 1 EtOAc: hexane to EtOAc) to obtain (S, E) -3- (2 ', 2'-dimethyldodec-4'-enoyl) aminocaprolactam (2.12 g; 63%) ;

(c = 1, CHCl ₃ ) +21.6; n _max / cm ^-1 3264 (NH), 1639 (CO), 1497 (NH); d _H (500 MHz, CDCl ₃ ) 7.09 (1H, d, J 5.5, CHN H ), 6.67-6.32 (1H, broad m, CH ₂ N H ), 5.42 ( 1H, dt, J 15, 6.5, C H = CH), 5.28 (1H, dt, J 15, 7, CH = C H ), 4.44 (1H, dd, J 11, 5.5 , C H NH), 3.30-3.17 (2H, m, C H ₂ NH), 2.20 (1H, dd, 13.5, 7, CH = CHC H ₂ ), 2.14 (1H dd, 13.5, 7, CH = CHC H ₂ ), 2.01-1.87 (4H, broad m, ring CH × 2, + C H ₂ CH = CH), 1.87-1, 74 (2H, m, CH ring), 1.47-1.32 (2H, m, CH ring), 1.27-1.15 (10H, m, (CH ₂ ) ₅ ) 1.13 ( 3H, s, CM e Me), 1.12 (3H, s, CMe Me ) and 0.83 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 176.8, 176.0 (CO), 134.2, 125.2 (CH = CH), 52.1 (NH C HCO), 43.9 (CH ₂ ), 42.1 (× 2) (CH ₂ + CM e ₂ ), 32.6, 31.8, 31.5, 30.1, 29.4, 29.1 (× 2), 28.9, 27, 9 (CH ₂ ), 25.0, 24.8 (CH ₃ ) and 22.6 (CH ₃ ); m / z (MH ⁺ C ₂₀ H ₃₇ N ₂ O ₂ requires 337.2855) 337.2858.

Example 23: (S) -3- (2 ', 2', 5'-trimethylhex-4'-enoyl) aminocaprolactam :

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (4.11 g, 16 mmol) and

(c = 1, CHCl₃) +23,2; n_max/см^-1 3394, 3251 (NH), 1674, 1633 (CO), 1503 (NH); d_H (500 МГц, CDCl₃) 7,11 (1H, д, J 5,0, CHNH), 6,65-6,45 (1H, шир.м, CH₂NH), 5,04 (1H, т, J 7,5, CH=C), 4,44 (1H, ддд, J 11, 5,5, 1,5, CHNH), 3,24-3,16 (2H, м, CH ₂NH), 2,20 (1H, дд, J 14,5, 7,5, C=CHCH ₂), 2,15 (1H, дд, J, 14,5, 7,5, C=CHCH₂), 2,03-1,90 (2H, м, 2 × кольцо CH), 1,84-1,72 (2H, м, 2 × кольцо CH), 1,65 (3H, с, CH₃), 1,56 (3H, с, CH₃), 1,45-1,28 (2H, м, 2 × кольцо CH), 1,13 (3H, с, CH₃) и 1,12 (3H, с, CH₃); d_C (125 МГц, CDCl₃) 176,9, 176,0 (CO), 134,1, 119,9 (CH=CH), 52,1 (NHCHCO), 42,5 (CH₂ СМe₂), 42,1 (CH₂N), 39,0, 31,5, 28,9, 28,0 (CH₂ лактам), 26,0, 25,0, 24,9, 17,9 (CH₃); m/z (МH⁺ C₁₅H₂₇N₂O₂ требует 267,2073) 267,2063.Na ₂ CO ₃ (5.09 g, 48 mmol) in water (50 ml) was added to a solution of 2,2,5-trimethylhex-4-enoyl chloride (16 mmol) in dichloromethane (50 ml) at ambient temperature and the reaction mixture stirred for 12 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 50 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (1: 5 EtOAc: hexanes to EtOAc) to obtain (S) -3- (2 ', 2', 5'-trimethylhex-4'-enoyl) aminocaprolactam as a waxy solid (3 58g; 84%); melting point 43-44 ° C;

(c = 1, CHCl ₃ ) +23.2; n _max / cm ^-1 3394, 3251 (NH), 1674, 1633 (CO), 1503 (NH); d _H (500 MHz, CDCl ₃ ) 7.11 (1H, d, J 5.0, CHN H ), 6.65-6.45 (1H, broad m, CH ₂ N H ), 5.04 ( 1H, t, J 7.5, CH = C), 4.44 (1H, ddd, J 11, 5.5, 1.5, C H NH), 3.24-3.16 (2H, m, C H ₂ NH), 2.20 (1H, dd, J 14.5, 7.5, C = CHC H ₂ ), 2.15 (1H, dd, J , 14.5, 7.5, C = CHCH ₂ ), 2.03-1.90 (2H, m, 2 × CH ring), 1.84-1.72 (2H, m, 2 × CH ring), 1.65 (3H, s, CH ₃ ), 1.56 (3H, s, CH ₃ ), 1.45-1.28 (2H, m, 2 × CH ring), 1.13 (3H, s, CH ₃ ) and 1.12 (3H, s, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 176.9, 176.0 (CO), 134.1, 119.9 (CH = CH), 52.1 (NH C HCO), 42.5 (CH ₂ CM e ₂ ), 42.1 (CH ₂ N), 39.0, 31.5, 28.9, 28.0 (CH ₂ lactam), 26.0, 25.0, 24.9, 17.9 (CH ₃ ); m / z (MH ⁺ C ₁₅ H ₂₇ N ₂ O ₂ requires 267.2073) 267.2063.

(c = 1, CHCl₃) +27,8; n_max/см^-1 3249 (NH), 1654, 1638 (CO), 1502 (NH); d_H (500 МГц, CDCl₃) 7,08 (1H, д, J 5,0, CHNH), 6,75-6,55 (1H, шир.м, CH₂NH), 4,44 (1H, ддд, J 11, 5,5, 1,5, CHNH), 3,29-3,16 (2H, м, CH ₂NH), 2,03-1,91 (2H, м, 2 × кольцо CH), 1,84-1,73 (2H, м, 2 × кольцо CH), 1,47-1,28 (5H, м, 2 × кольцо CH + CH₂ + CH(CH₃)₂), 1,13 (3H, с, CH₃), 1,12 (3H, с, CH₃), 1,08-1,02 (2H, м, CH₂), 0,82 (3H, с, CH₃), 0,80 (3H, с, CH₃); d_C (125 МГц, CDCl₃) 177,1, 176,1 (CO), 52,1 (NHCHCO), 42,1 (CH₂N), 41,9 (CH₂ СМe₂), 39,0, 33,7, 31,5, 28,9 (CH₂), 28,4 (Мe₂ CH), 27,9 (CH₂), 25,3, 25,2, 22,6, 22,5 (CH₃); m/z (МH⁺ C₁₅H₂₉N₂O₂ требует 269,2229) 269,2219. Example 24: (S) -3- (2 ', 2', 5'-trimethylhexanoyl) aminocaprolactam : (S) -3- (2 ', 2', 5'-trimethylhex-4'-enoyl) aminocaprolactam (400 mg ) was dissolved in EtOAc (25 ml), palladium hydroxide on carbon (20%, about 100 mg) was added and the mixture was stirred at ambient temperature under a hydrogen atmosphere for 14 hours. Then the reaction mixture was filtered through a Celite® layer and the solvent was removed in vacuo to obtain (S) -3- (2 ', 2', 5'-trimethylhexanoyl) aminocaprolactam as a waxy solid (400 mg, 98%); melting point 73-74 ° C.

(c = 1, CHCl ₃ ) +27.8; n _max / cm ^-1 3249 (NH), 1654, 1638 (CO), 1502 (NH); d _H (500 MHz, CDCl ₃ ) 7.08 (1H, d, J 5.0, CHN H ), 6.75-6.55 (1H, broad m, CH ₂ N H ), 4.44 ( 1H, ddd, J 11, 5.5, 1.5, C H NH), 3.29-3.16 (2H, m, C H ₂ NH), 2.03-1.91 (2H, m, 2 × CH ring), 1.84-1.73 (2H, m, 2 × CH ring), 1.47-1.28 (5H, m, 2 × CH + CH ₂ + C H (CH ₃ ) ring ₂ ), 1.13 (3H, s, CH ₃ ), 1.12 (3H, s, CH ₃ ), 1.08-1.02 (2H, m, CH ₂ ), 0.82 (3H, s , CH ₃ ), 0.80 (3H, s, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 177.1, 176.1 (CO), 52.1 (NH C HCO), 42.1 (CH ₂ N), 41.9 (CH ₂ CM e ₂ ), 39 0, 33.7, 31.5, 28.9 (CH ₂ ), 28.4 (Me ₂ C H), 27.9 (CH ₂ ), 25.3, 25.2, 22.6, 22 5 (CH ₃ ); m / z (MH ⁺ C ₁₅ H ₂₉ N ₂ O ₂ requires 269.2229) 269.2219.

Example 25: (S) -3- (11'-bromundecanoyl) aminocaprolactam :

(c = 1, CHCl₃) +31,8; n_max/см^-1 3342, 3287 (NH), 1668, 1634 (CO), 1515 (NH); d_H (500 МГц, d₆-ДМСО) 7,76 (1H, т, J 6,5, CH₂NH), 7,67 (1H, д, J 7, CHNH), 4,38 (1H, дд, J 11, 7, CHNH), 3,51 (2H, т, J 6,5, CH₂Br,), 3,15 (1H, ддд, J 15,5, 10,5, 5, CHHNH), 3,05 (1H, дт, J 14, 7, CHHNH), 2,17-2,06 (2H, м, CH ₂CONH), 1,85 (1H, дт, J 14, 3, C-5 H), 1,82-1,68 (4H, м, C-4 H, C-6 H и CH ₂CH₂Br,), 1,62 (1H, кт, J 12, 3,5, C-5 H), 1,46 (2H, шир.кн J 6,5, CH ₂CH₂CONH), 1,41-1,31 (3H, м, C-4 H и цепь CH₂) и 1,31-1,13 (11H, м, (CH₂)₅ + C-6 H); d_C (125 МГц, d₆-ДМСО) 174,4 (CO-кольцо), 171,3 (CO-цепь), 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 и 25,4 (CH₂); m/z (МH⁺ BrC₁₇H₃₂N₂O₂ требует 375,1647) 375,1655.(S) -3-aminocaprolactam hydrochloride (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (25 ml) are added to a solution of 11-bromundecanoyl chloride (5 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture stirred for 4 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give (S) -3- (11'-bromundecanoyl) aminocaprolactam (1.49 g; 79%); melting point (EtOAc) 73-74 ° C;

(c = 1, CHCl ₃ ) +31.8; n _max / cm ^-1 3342, 3287 (NH), 1668, 1634 (CO), 1515 (NH); d _H (500 MHz, d ₆ -DMSO) 7.76 (1H, t, J 6.5, CH ₂ N H ), 7.67 (1H, d, J 7, CHN H ), 4.38 (1H dd, J 11, 7, C H NH), 3.51 (2H, t, J 6.5, CH ₂ Br,), 3.15 (1H, ddd, J 15.5, 10.5, 5 , C H HNH), 3.05 (1H, dt, J 14, 7, CH H NH), 2.17-2.06 (2H, m, C H ₂ CONH), 1.85 (1H, dt, J 14, 3, C-5 H), 1.82-1.68 (4H, m, C-4 H, C-6 H and C H ₂ CH ₂ Br,), 1.62 (1H, qt, J 12, 3.5, C-5 H), 1.46 (2H, br J 6.5, C H ₂ CH ₂ CONH), 1.41-1.31 (3H, m, C-4 H and a CH ₂ chain) and 1.31-1.13 (11H, m, (CH ₂ ) ₅ + C-6 H); d _C (125 MHz, d ₆ -DMSO) 174.4 (CO ring), 171.3 (CO chain), 51.3 (NH C HCO), 40.7 (NCH ₂ ), 35.3, 35.2, 32.4, 31.3, 29.0, 28.9 (× 3), 28.7, 28.2, 27.8, 27.6 and 25.4 (CH ₂ ); m / z (MH ⁺ BrC ₁₇ H ₃₂ N ₂ O ₂ requires 375.1647) 375.1655.

Example 26: (S) -3- (11'-azidooundecanoyl) aminocaprolactam :

(c = 1, CHCl₃) +34,7; n_max/см^-1 3344, 3289 (NH), 2101 (N₃) 1668, 1631 (CO), 1516 (NH); d_H (500 МГц, d₆-ДМСО) 7,77 (1H, т, J 6, CH₂NH), 7,67 (1H, д, J 7, CHNH), 4,38 (1H, дд, J 11, 7, CHNH), 3,30 (2H, т, J 7, CH₂N₃), 3,15 (1H, ддд, J 15,5, 10,5, 5, CHHNH), 3,05 (1H, дт, J 14, 5,5, CHHNH), 2,17-2,07 (2H, м, CH ₂CONH), 1,85 (1H, дт, J 14, 3,5, C-5 H), 1,82-1,68 (2H, м, C-4 H, C-6 H), 1,62 (1H, кт, J 13, 3,5, C-5 H), 1,51 (4H, м, CH ₂CH₂CONH и CH ₂CH₂N₃), 1,36 (1H, кд, J 13, 3, C-4 H), и 1,33-1,13 (13H, м, (CH₂)₆ + C-6 H); d_C (125 МГц, d₆-ДМСО) 174,4 (CO-кольцо), 171,3 (CO-цепь), 51,3 (NHCHCO), 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 и 25,4 (CH₂); m/z (МNa⁺ C₁₇H₃₁N₅O₂Na требует 360,2375) 360,2360.Sodium azide (650 mg, 10 mmol) was added to (S) -3- (11-bromundecanoyl) aminocaprolactam (375 mg, 1 mmol) in DMF (2 ml) and the mixture was heated at 60 ° C. for 14 hours. Then, the solvent removed in vacuo and the residue partitioned between water (20 ml) and EtOAc (3 x 20 ml). The combined organic layers were washed with 1 M HCl _aq (2 x 20 ml) and then dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give (S) -3- (11'-azidoundecanoyl) aminocaprolactam (221 mg; 66%); melting point (EtOAc) 71-72 ° C;

(c = 1, CHCl ₃ ) +34.7; n _max / cm ^-1 3344, 3289 (NH), 2101 (N ₃ ) 1668, 1631 (CO), 1516 (NH); d _H (500 MHz, d ₆ -DMSO) 7.77 (1H, t, J 6, CH ₂ N H ), 7.67 (1H, d, J 7, CHN H ), 4.38 (1H, dd , J 11, 7, C H NH), 3.30 (2H, t, J 7, CH ₂ N ₃ ), 3.15 (1H, ddd, J 15.5, 10.5, 5, C H HNH ), 3.05 (1H, dt, J 14.5.5, CH H NH), 2.17-2.07 (2H, m, C H ₂ CONH), 1.85 (1H, dt, J 14 3.5, C-5 H), 1.82-1.68 (2H, m, C-4 H, C-6 H), 1.62 (1H, qt, J 13, 3.5, C -5 H), 1.51 (4H, m, C H ₂ CH ₂ CONH and C H ₂ CH ₂ N ₃ ), 1.36 (1H, cd, J 13, 3, C-4 H), and 1 33-1.13 (13H, m, (CH ₂ ) ₆ + C-6 H); d _C (125 MHz, d ₆ -DMSO) 174.4 (CO ring), 171.3 (CO chain), 51.3 (NH C HCO), 50.7 (CH ₂ N ₃ ), 40, 7 (NCH ₂ ), 35.3, 31.3, 29.0 (× 2), 28.9, 28.7, 28.6, 28.3, 27.8, 26.2 and 25.4 ( CH ₂ ); m / z (MNa ⁺ C ₁₇ H ₃₁ N ₅ O ₂ Na requires 360.2375) 360.2360.

Example 27: (S) 11'-sulfonate tetrahydrate sodium-3- (undecanoyl) aminocaprolactam:

(c = 1, H₂O) -15,5; n_max/см^-1 3430, 3344, 3289 (NH + H₂O), 1667, 1643 (CO), 1530 (NH) 1195, 1183 (СO₃, асимметричн.), 1064 (СO₃, симметричн.); d_H (500 МГц, d₆-ДМСО) 7,76 (1H, т, J 6, CH₂NH), 7,70 (1H, д, J 7, CHNH), 4,35 (1H, дд, J 10, 7,5, CHNH), 3,42 (8H, с, 4 × H₂O) 3,17-3,00 (2H, м, CH ₂NH), 2,47-2,38 (2H, м, CH₂СO₃), 2,17-2,05 (2H, м, CH ₂CONH), 1,82 (1H, шир.с, J 13,5, C-5 H), 1,75-1,66 (2H, м, C-4 H, C-6 H), 1,65-1,50 (3H, м, C-5 H + цепь CH₂), 1,47-1,40 (2H, м, цепь CH₂) 1,35 (1H, кд, J 13, 3, C-4 H), и 1,30-1,11 (13H, м, (CH₂)₆ + C-6 H); d_C (125 МГц, d₆-ДМСО) 174,5 (CO-кольцо), 171,5 (CO-цепь), 51,6 (CH₂СO₃), 51,4 (NHCHCO), 40,8 (NCH₂), 35,3, 31,3, 29,1 (×3), 29,0 (×2), 28,8, 28,6, 27,8, 25,5 и 25,1 (CH₂); m/z (МNa⁺ C₁₇H₃₁N₂O₅SNa₂ требует 421,1749) 421,1748.Sodium sulfite (630 mg, 5 mmol) in water (3 ml) was added to (S) -3- (11-bromundecanoyl) aminocaprolactam (375 mg, 1 mmol) in ethanol (2 ml), and the mixture was refluxed for 14 h. The cooled reaction mixture was then added to ethanol (25 ml) and the reaction mixture was filtered. Then, the solvent was removed in vacuo to give (S) 11'-sulfonate tetrahydrate sodium-3- (undecanoyl) aminocaprolactam (456 mg; 97%); melting point (EtOAc) 208-210 ° C;

(c = 1, H ₂ O) -15.5; n _max / cm ^-1 3430, 3344, 3289 (NH + H ₂ O), 1667, 1643 (CO), 1530 (NH) 1195, 1183 (CO ₃ asymmetric), 1064 (CO ₃ symmetrical); d _H (500 MHz, d ₆ -DMSO) 7.76 (1H, t, J 6, CH ₂ N H ), 7.70 (1H, d, J 7, CHN H ), 4.35 (1H, dd , J 10, 7.5, C H NH), 3.42 (8H, s, 4 × H ₂ O) 3.17-3.00 (2H, m, C H ₂ NH), 2.47-2 38 (2H, m, CH ₂ CO ₃ ), 2.17-2.05 (2H, m, C H ₂ CONH), 1.82 (1H, broad s, J 13.5, C-5 H ), 1.75-1.66 (2H, m, C-4 H, C-6 H), 1.65-1.50 (3H, m, C-5 H + CH ₂ chain), 1.47 -1.40 (2H, m, CH ₂ chain) 1.35 (1H, cd, J 13, 3, C-4 H), and 1.30-1.11 (13H, m, (CH ₂ ) ₆ + C-6 H); d _C (125 MHz, d ₆ -DMSO) 174.5 (CO ring), 171.5 (CO chain), 51.6 (CH ₂ CO ₃ ), 51.4 (NH C HCO), 40, 8 (NCH ₂ ), 35.3, 31.3, 29.1 (× 3), 29.0 (× 2), 28.8, 28.6, 27.8, 25.5 and 25.1 ( CH ₂ ); m / z (MNa ⁺ C ₁₇ H ₃₁ N ₂ O ₅ SNa ₂ requires 421.1749) 421.1748.

Example 28: (S) -3- (decansulfonyl) aminocaprolactam :

(c = 1, МeOH) +22,7; n_max/см^-1 3365, 3248 (NH), 1657 (CO), 1324, 1142 (SO₂N); d_H (500 МГц, CDCl₃) 6,35-6,18 (1H, м, CH₂NH), 5,71 (1H, д, J 6, CHNH), 4,11 (1H, ддд, J 11,5, 6, 2, CHNH), 3,31-3,18 (2H, м, CH ₂NH), 2,98-2,92 (2H, м, CH₂СO₂), 2,09 (1H, шир.д, J 14, кольцо CH), 2,06-1,97 (1H, м, кольцо CH), 1,88-1,59 (5H, м, CH ₂CH₂SO₂ + 3 кольцо CH), 1,43-1,33 (3H, м, цепь CH₂ + кольцо CH), 1,32-1,18 (12H, м, CH₃(CH₂)₆) и 0,86 (3H, м, CH₃); d_C (125 МГц, CDCl₃) 174,8 (CO) 55,5 (NHCHCO), 53,5 (CH₂СO₂), 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) и 14,1 (CH₃); m/z (МNa⁺ C₁₆H₃₂N₂O₃SNa требует 355,2031) 355,2054; аналитич. (C₁₆H₃₂N₂O₃S требует C, 57,8, H, 9,7, N, 8,4) C, 57,8, H, 9,7, N, 8,3.(S) -3-aminocaprolactam hydrochloride (3 mmol) and Na ₂ CO ₃ (9 mmol) in water (20 ml) are added to a solution of decansulfonyl chloride (3 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred in for 10 hours, then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc / hexanes to give (S) -3- (decanesulfonyl) aminocaprolactam (481 mg; 48%); melting point 98-99 ° C;

(c = 1, MeOH) +22.7; n _max / cm ^-1 3365, 3248 (NH), 1657 (CO), 1324, 1142 (SO ₂ N); d _H (500 MHz, CDCl ₃ ) 6.35-6.18 (1H, m, CH ₂ N H ), 5.71 (1H, d, J 6, CHN H ), 4.11 (1H, ddd, J 11.5, 6, 2, C H NH), 3.31-3.18 (2H, m, C H ₂ NH), 2.98-2.92 (2H, m, CH ₂ CO ₂ ), 2.09 (1H, brd, J 14, CH ring), 2.06-1.97 (1H, m, CH ring), 1.88-1.59 (5H, m, C H ₂ CH ₂ SO ₂ + 3 ring CH), 1.43-1.33 (3H, m, CH ₂ chain + CH ring), 1.32-1.18 (12H, m, CH ₃ (CH ₂ ) ₆ ) and 0 86 (3H, m, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 174.8 (CO) 55.5 (NH C HCO), 53.5 (CH ₂ CO ₂ ), 40.7 (NCH ₂ ), 33.9, 31.8, 29.4, 29.3, 29.2, 29.1, 28.6, 28.3, 27.9, 23.5, 22.6 (CH ₂ ) and 14.1 (CH ₃ ); m / z (MNa ⁺ C ₁₆ H ₃₂ N ₂ O ₃ SNa requires 355.2031) 355.2054; analytic (C ₁₆ H ₃₂ N ₂ O ₃ S requires C, 57.8, H, 9.7, N, 8.4) C, 57.8, H, 9.7, N, 8.3.

Example 29: (S) -3- (dodecansulfonyl) aminocaprolactam :

(c = 1, МeOH) +22,4; n_max/см^-1 3366, 3247 (NH), 1657 (CO), 1324, 1143 (SO₂N); d_H (500 МГц, CDCl₃) 6,66 (1H, т, J 6, CH₂NH), 5,78 (1H, д, J 6, CHNH), 4,10 (1H, ддд, J 11, 6, 2, CHNH), 3,29-3,17 (2H, м, CH ₂NH), 2,97-2,90 (2H, м, CH₂SO₂), 2,12-2,03 (1H, м, кольцо CH), 2,03-1,96 (1H, м, кольцо CH), 1,88-1,59 (5H, м, CH ₂CH₂SO₂ + 3 кольцо CH), 1,43-1,32 (3H, м, кольцо CH + цепь CH₂), 1,32-1,18 (16H, м) и 0,85 (3H, м, CH₃); d_C (125 МГц, 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) и 14,1 (CH₃); m/z (МNa⁺ C₁₈H₃₆N₂O₃SNa требует 383,2339) 383,2351; аналитич. (C₁₈H₃₆N₂O₃S требует C, 60,0, H, 10,1, N, 7,8) C, 59,9, H, 10,2, N, 7,7.(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (20 ml) are added to a solution of dodecane sulfonyl chloride (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred in for 10 hours, then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexanes: EtOAc 3: 1 to 100% EtOAc) and then recrystallized from heptane to obtain (S) -3- (dodecansulfonyl) aminocaprolactam (302 mg; 42%); melting point 100-101 ° C;

(c = 1, MeOH) +22.4; n _max / cm ^-1 3366, 3247 (NH), 1657 (CO), 1324, 1143 (SO ₂ N); d _H (500 MHz, CDCl ₃ ) 6.66 (1H, t, J 6, CH ₂ N H ), 5.78 (1H, d, J 6, CHN H ), 4.10 (1H, ddd, J 11, 6, 2, C H NH), 3.29-3.17 (2H, m, C H ₂ NH), 2.97-2.90 (2H, m, CH ₂ SO ₂ ), 2.12 -2.03 (1H, m, CH ring), 2.03-1.96 (1H, m, CH ring), 1.88-1.59 (5H, m, C H ₂ CH ₂ SO ₂ + 3 ring CH), 1.43-1.32 (3H, m, ring CH + chain CH ₂ ), 1.32-1.18 (16H, m) and 0.85 (3H, m, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 175.0 (CO) 55.5 (NH C HCO), 53.5 (CH ₂ SO ₂ ), 42.1 (NCH ₂ ), 33.8, 31.8, 29.6 (× 2), 29.5, 29.3 (× 2), 29.1, 28.6, 28.3, 27.9, 23.5, 22.6 (CH ₂ ) and 14, 1 (CH ₃ ); m / z (MNa ⁺ C ₁₈ H ₃₆ N ₂ O ₃ SNa requires 383.2339) 383.2351; analytic (C ₁₈ H ₃₆ N ₂ O ₃ S requires C, 60.0, H, 10.1, N, 7.8) C, 59.9, H, 10.2, N, 7.7.

Example 30: (S) -3- (tetradecanesulfonyl) aminocaprolactam :

(c = 1, CHCl₃) +14,4; n_max/см^-1 3361, 3250 (NH), 1658 (CO), 1324, 1140 (SO₂N); d_H (500 МГц, CDCl₃) 6,64 (1H, т, J 6, CH₂NH), 5,74 (1H, д, J 6, CHNH), 4,11 (1H, ддд, J 11,5, 6, 2, CHNH), 3,30-3,17 (2H, м, CH ₂NH), 2,97-2,92 (2H, м, CH₂SO₂), 2,12-2,05 (1H, м, кольцо CH), 2,05-1,96 (1H, м, кольцо CH), 1,87-1,59 (5H, м, CH ₂CH₂SO₂ + 3 кольцо CH), 1,42-1,32 (3H, м, кольцо CH + цепь CH₂), 1,32-1,18 (20H, м, цепь CH₂) и 0,86 (3H, м, CH₃); d_C (125 МГц, CDCl₃) 174,9 (CO), 55,5 (NHCHCO), 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) и 14,1 (CH₃); m/z (МNa⁺ C₂₀H₄₀N₂O₃SNa требует 411,2652) 411,2655; аналитич. (C₂₀H₄₀N₂O₃S требует C, 61,8, H, 10,4, N, 7,2) C, 61,9, H, 10,5, N, 7,2.(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (20 ml) are added to a solution of tetradecane sulfonyl chloride (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred in for 10 hours, then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexanes: EtOAc 3: 1 to 100% EtOAc) and then recrystallized from heptane to obtain (S) -3- (tetradecansulfonyl) aminocaprolactam (373 mg; 48%); melting point 100-101 ° C;

(c = 1, CHCl ₃ ) +14.4; n _max / cm ^-1 3361, 3250 (NH), 1658 (CO), 1324, 1140 (SO ₂ N); d _H (500 MHz, CDCl ₃ ) 6.64 (1H, t, J 6, CH ₂ N H ), 5.74 (1H, d, J 6, CHN H ), 4.11 (1H, ddd, J 11.5, 6, 2, C H NH), 3.30-3.17 (2H, m, C H ₂ NH), 2.97-2.92 (2H, m, CH ₂ SO ₂ ), 2 12-2.05 (1H, m, CH ring), 2.05-1.96 (1H, m, CH ring), 1.87-1.59 (5H, m, C H ₂ CH ₂ SO ₂ + 3 CH ring), 1.42-1.32 (3H, m, CH ring + CH ₂ chain), 1.32-1.18 (20H, m, CH ₂ chain) and 0.86 (3H, m , CH ₃ ); d _C (125 MHz, CDCl ₃ ) 174.9 (CO), 55.5 (NH C HCO), 53.4 (CH ₂ SO ₂ ), 42.2 (NCH ₂ ), 33.8, 31.9 , 29.6 (× 4), 29.5, 29.3 (× 2), 29.1, 28.6, 28.3, 27.9, 23.5, 22.7 (CH ₂ ) and 14 , 1 (CH ₃ ); m / z (MNa ⁺ C ₂₀ H ₄₀ N ₂ O ₃ SNa requires 411.2652) 411.2655; analytic (C ₂₀ H ₄₀ N ₂ O ₃ S requires C, 61.8, H, 10.4, N, 7.2) C, 61.9, H, 10.5, N, 7.2.

Example 31: (S) -3- (hexadecane sulfonyl) aminocaprolactam :

(c = 1, CHCl₃) +14,1; n_max/см^-1 3356, 3249 (NH), 1659 (CO), 1323, 1140 (SO₂N); d_H (500 МГц, CDCl₃) 6,55 (1H, т, J 6, CH₂NH), 5,76 (1H, д, J 6, CHNH), 4,11 (1H, ддд, J 11,5, 6, 2, CHNH), 3,30-3,17 (2H, м, CH ₂NH), 2,94 (2H, т, J 8, CH₂SO₂), 2,12-2,04 (1H, м, кольцо CH), 2,04-1,97 (1H, м, кольцо CH), 1,87-1,58 (5H, м, CH ₂CH₂SO₂ + 3 кольцо CH), 1,42-1,32 (3H, м, кольцо CH + цепь CH₂), 1,32-1,18 (24H, м, цепь CH₂) и 0,86 (3H, м, CH₃); d_C (125 МГц, 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) и 14,1 (CH₃); m/z (МNa⁺ C₂₀H₄₀N₂O₃SNa требует 439,2965) 439,2980; аналитич. (C₂₂H₄₄N₂O₃S требует C, 63,4, H, 10,6, N, 6,7) C, 63,1, H, 10,6, N, 6,6.(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (20 ml) are added to a solution of hexadecane sulfonyl chloride (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred in for 10 hours, then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexanes: EtOAc 3: 1 to 100% EtOAc) and then recrystallized from heptane to obtain (S) -3- (hexadecansulfonyl) aminocaprolactam (553 mg; 66%); melting point 100-101 ° C;

(c = 1, CHCl ₃ ) +14.1; n _max / cm ^-1 3356, 3249 (NH), 1659 (CO), 1323, 1140 (SO ₂ N); d _H (500 MHz, CDCl ₃ ) 6.55 (1H, t, J 6, CH ₂ N H ), 5.76 (1H, d, J 6, CHN H ), 4.11 (1H, ddd, J 11.5, 6, 2, C H NH), 3.30-3.17 (2H, m, C H ₂ NH), 2.94 (2H, t, J 8, CH ₂ SO ₂ ), 2, 12-2.04 (1H, m, CH ring), 2.04-1.97 (1H, m, CH ring), 1.87-1.58 (5H, m, C H ₂ CH ₂ SO ₂ + 3 ring CH), 1.42-1.32 (3H, m, ring CH + chain CH ₂ ), 1.32-1.18 (24H, m, chain CH ₂ ) and 0.86 (3H, m, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 174.9 (CO), 55.5 (NH C HCO), 53.5 (CH ₂ SO ₂ ), 42.1 (NCH ₂ ), 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 (CH ₂ ) and 14.1 (CH ₃ ); m / z (MNa ⁺ C ₂₀ H ₄₀ N ₂ O ₃ SNa requires 439.2965) 439.2980; analytic (C ₂₂ H ₄₄ N ₂ O ₃ S requires C, 63.4, H, 10.6, N, 6.7) C, 63.1, H, 10.6, N, 6.6.

Example 32: (S) -3- (octadecanesulfonyl) aminocaprolactam :

(S) -3-aminocaprolactam hydrochloride (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (20 ml) are added to a solution of octadecane sulfonyl chloride (2 mmol) in dichloromethane (20 ml) at ambient temperature and the reaction mixture is stirred in for 10 hours, then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexanes: EtOAc 3: 1 to 100% EtOAc) and then recrystallized from heptane to obtain (S) -3- (octadecansulfonyl) aminocaprolactam (545 mg; 61%); melting point 99-100 ° C; n _max / cm ^-1 3356, 3249 (NH), 1659 (CO), 1323, 1140 (SO ₂ N); d _H (500 MHz, CDCl ₃ ) 6.15 (1H, t, J 6, CH ₂ N H ), 5.69 (1H, d, J 6, CHN H ), 4.12 (1H, ddd, J 11.5, 6, 2, C H NH), 3.30-3.18 (2H, m, C H ₂ NH), 2.97-2.92 (2H, m, CH ₂ CO ₂ ), 2 12-2.07 (1H, m, CH ring), 2.06-1.97 (1H, m, CH ring), 1.87-1.56 (5H, m, C H ₂ CH ₂ SO ₂ + 3 CH ring), 1.42-1.32 (3H, m, CH ring + CH ₂ chain), 1.32-1.18 (28H, m, CH ₂ chain) and 0.86 (3H, m , CH ₃ ); m / z (MNa ⁺ C ₂₄ H ₄₈ N ₂ O ₃ SNa requires 467.3277852) 467.330047.

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

This tripeptide is obtained on a solid-phase automated peptide synthesizer using (S) -aminocaprolactam at the final stage of peptide condensation. Mr (relative molecular weight) (calculated) = 471.5110. Observed Mr according to mass spectrometry 471.6. Purity (% TIC (trypsin-inhibiting activity) at molecular ion peak) = 90%.

Example 34: (S) -aminocaprolactam- (L) -valine- (L) -deaminotryptophan :

This tripeptide is obtained on a solid-phase automated peptide synthesizer using (S) -aminocaprolactam at the final stage of peptide condensation. Mr (calculated) = 398.4600. Observed Mr according to mass spectrometry 398.3. Purity (% TIC (trypsin-inhibiting activity) at molecular ion peak) = 96%.

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

Example 35 :

Intermediate compound

(E) -methyl-2,2-dimethyldodec-4-enoate:

Butyllithium (3.8 M, 10 mmol) was added to a solution of diisopropylamine (1.42 ml, 10 mmol) in dry THF at -78 ° C in an atmosphere of N ₂ . The reaction mixture was stirred at -78 ° C for 20 minutes and then methyl isobutyrate (1.15 ml, 10 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 h, and then (E) -dec-2-enyl bromide (2.19 g, 10 mmol) was added and the reaction mixture was allowed to warm to ambient temperature for 14 hours. The reaction solvent then removed in vacuo and the residue partitioned between aqueous buffer at pH 2 (0.5 M NaHSO ₄ / 0.5 M Na ₂ SO ₄ ) (100 ml) and hexane (3 x 100 ml). The combined organic layers were dried over Na ₂ SO ₄ and the hexane solvent was removed in vacuo to give crude (E) -methyl-2,2-dimethyldodec-4-enoate (with a purity> 90%) (2.27 g) as a colorless oil ; n _max / cm ^-1 1734 (CO); d _H (400 MHz, CDCl ₃ ) 5.42 (1H, broad dt, J 15, 6.5, C H = CH), 5.30 (1H, dtt, J 15, 7, 1, CH = C H ), 3.64 (3H, s, OCH ₃ ), 2.18 (2H, dd, J 7, 1, C H ₂ CMe ₂ ), 1.96 (2H, broad s, J 6.5, CH ₂ C H ₂ CH = CH), 1.35-1.20 (10H, m, (C H ₂ ) ₅ CH ₃ ), 1.14 (6H, s, C (C H ₃ ) ₂ ), 0 87 (3H, t, J 6.5, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 178.2 (CO), 134.1, 125.2 (HC = CH), 51.5 (OCH ₃ ), 43.6 (CH ₂ ), 42.6 (Me ₂ C CO), 32.6, 31.8, 29.5, 29.1, 29.0 (CH ₂ ), 24.7 (C ( C H ₃ ) × 2), 22.6 (CH ₂ ) 14.1 (CH ₂ C H ₃ ); m / z (MH ⁺ C ₁₅ H ₂₉ N ₂ O ₂ requires 241.2168) 241.2169.

Example 36 :

Intermediate compound

(E) -2,2-dimethyldodec-4-enoyl chloride:

The entire product from the above reaction was then dissolved in ethanol (50 ml) and added to a solution of NaOH (2.0 g, 50 mmol) in water (25 ml). The mixture was refluxed for 6 hours, allowed to cool, and the solvents were then removed in vacuo. The residue was partitioned between aqueous buffer at pH 2 (0.5 M NaHSO ₄ / 0.5 M Na ₂ SO ₄ ) (100 ml) and diethyl ether (3 x 100 ml). The combined organic layers were dried over Na ₂ CO ₃ and the ethereal solvent was removed in vacuo to give crude (E) -2,2-dimethyldodec-4-enoic acid (with a purity> 90%) (2.27 g) as a colorless oil; d _H (400 MHz, CDCl ₃ ) 5.46 (1H, broad dt, J 15, 6.5, C H = CH), 5.35 (1H, dtt, J 15, 7, 1, CH = C H ), 2.22 (2H, dd, J 7, 1, C H ₂ CMe ₂ ), 1.98 (2H, br. J, 6.5, CH ₂ C H ₂ CH = CH), 1, 37-1.21 (10H, m, (C H ₂ ) ₅ CH ₃ ), 1.17 (6H, s, C (C H ₃ ) ₂ ), 0.87 (3H, t, J 6.5, CH ₂ C H ₃ ) . The crude acid is dissolved in dichloromethane (50 ml) and oxalyl chloride (3 ml) is added along with a drop of DMF. The reaction mixture was stirred for 1 h and the solvent was removed in vacuo to give crude (E) -2,2-dimethyldodec-4-enoyl chloride, which was used whole without purification in the next step.

Example 37 :

Intermediate compound

Methyl 2,2,5-trimethylhex-4-enoate:

Butyllithium (2.9 M, 50 mmol) was added to a solution of diisopropylamine (7.2 ml, 50 mmol) in dry THF at -78 ° C in an atmosphere of N ₂ . The reaction mixture was stirred at -78 ° C for 20 minutes and then methyl isobutyrate (5.7 ml, 50 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 h, and then 3-methylbut-2-enyl bromide (5.8 ml, 50 mmol) was added and the reaction mixture was allowed to warm to ambient temperature for 14 hours. The reaction solvent was then removed in vacuo and the residue partitioned between aqueous buffer at pH 2 (0.5 M NaHSO ₄ / 0.5 M Na ₂ SO ₄ ) (100 ml) and hexane (3 x 250 ml). The combined organic layers were dried over Na ₂ SO ₄ and the hexane solvent was removed in vacuo to give methyl 2,2,5-trimethylhex-4-enoate as a colorless oil (6.93 g, 81%); n _max / cm ^-1 1732 (CO); d _H (400 MHz, CDCl ₃ ) 5.04 (1H, tsept, J 7.5, 1.5, CH = C), 3.63 (3H, s, OCH ₃ ), 2.20 (2H, d , J 7.5, CHC H ₂ ), 1.68 (3H, br s, CH = CM e Me), 1.58 (3H, br s, CH = CM e Me ), 1.14 (6H, s, (CH ₃ ) ₂ CO); d _C (125 MHz, CDCl ₃ ) 178.4 (CO), 134.1 (Me ₂ C = CH), 119.8 (Me ₂ C = C H), 51.6 (OCH ₃ ), 42.8 (Me ₂ C CO), 38.7 (CH ₂ ), 25.9, 24.7 (× 2), 17.8 (C C H ₃ ); m / z (MH ⁺ C ₁₀ H ₁₉ O ₂ requires 171.1385) 171.1388.

Example 38 :

Intermediate compound

2,2,5-trimethylhex-4-enoyl chloride:

Methyl 2,2,5-trimethylhex-4-enoate (2.74 g, 16 mmol) was dissolved in ethanol (50 ml) and added to a solution of NaOH (3.0 g, 75 mmol) in water (35 ml). The mixture was refluxed for 6 hours, allowed to cool, and the solvents were then removed in vacuo. The residue was partitioned between an aqueous buffer at pH 2 (0.5 M NaHSO ₄ / 0.5 M Na ₂ SO ₄ ) and diethyl ether (3 x 150 ml). The combined organic layers were dried over Na ₂ SO ₄ and the ethereal solvent was removed in vacuo to give crude 2,2,5-trimethylhex-4-enoic acid (> 95% purity) as a colorless oil; d _H (400 MHz, CDCl ₃ ) 5.12 (1H, tsept, J 7.5, 1.5, CH = C), 2.25 (2H, d, J 7.5, CHC H ₂ ), 1 71 (3H, br s, CH = CM e Me), 1.60 (3H, br s, CH = CMe Me ), 1.18 (6H, s, (CH ₃ ) ₂ CO). The crude acid is dissolved in dichloromethane (50 ml) and oxalyl chloride (3 ml) is added along with a drop of DMF. The reaction mixture was stirred for 1 h and the solvent was removed in vacuo to give crude 2,2,5-trimethylhex-4-enoyl chloride, which was used whole without purification in the next step.

Example 39 :

This compound has two terminal groups of 2,2,6,6-tetramethylheptanoic acid on both sides. This results in a dimer of the corresponding 2.2-dimethyl compound of the invention:

(S, S) N, N'-bis- (2'-oxoazepan-3'-yl) -2,2,6,6-tetramethylheptadiamide:

(c = 1, CHCl₃) +29,4; n_max/см^-1 3379, 3255 (NH), 1683, 1637 (CO), 1507, 1497 (NH); d_H (500 МГц, CDCl₃) 7,07 (2H, д, J 5,5, CHNH), 6,42 (2H, шир.с, CH₂NH), 4,44 (2H, ддд, J 11, 5,5, 1,5, CHNH), 3,31-3,17 (4H, м, CH ₂NH), 2,04-1,94 (4H, м, кольцо CH), 1,86-1,73 (4H, м, кольцо CH), 1,51-1,31 (8H, шир.м, 2 × кольцо CH + CH ₂СМe₂) и 1,12 (14H, м, цепь CH₂CH ₂CH₂ + СМe ₂); d_C (125 МГц, CDCl₃) 176,9, 175,9 (CO), 52,1 (NHCH), 42,0 (СМe₂), 42,1, 41,5, 31,5, 28,9, 28,0 (CH₂), 25,3, 25,1 (CH₃) и 20,0 (CH₂); m/z (М⁺ C₂₃H₄₀N₄O₄ требует 436,30496) 436,30437.Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (25 ml) are added to a solution of 2,2,6,6-tetramethylheptanedioyl dichloride (1 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ CO ₃ and evaporated in vacuo. The residue was purified by recrystallization from EtOAc to give a (S, S) dimer (199 mg, 46%); melting point 234-236 ° C;

(c = 1, CHCl ₃ ) +29.4; n _max / cm ^-1 3379, 3255 (NH), 1683, 1637 (CO), 1507, 1497 (NH); d _H (500 MHz, CDCl ₃ ) 7.07 (2H, d, J 5.5, CHN H ), 6.42 (2H, br s, CH ₂ N H ), 4.44 (2H, ddd, J 11, 5.5, 1.5, C H NH), 3.31-3.17 (4H, m, C H ₂ NH), 2.04-1.94 (4H, m, CH ring), 1.86-1.73 (4H, m, CH ring), 1.51-1.31 (8H, br m, 2 × CH + C H ₂ CMe ₂ ring) and 1.12 (14H, m, chain CH ₂ C H ₂ CH ₂ + CM e ₂ ); d _C (125 MHz, CDCl ₃ ) 176.9, 175.9 (CO), 52.1 (NH C H), 42.0 ( CM e ₂ ), 42.1, 41.5, 31.5, 28.9, 28.0 (CH ₂ ), 25.3, 25.1 (CH ₃ ) and 20.0 (CH ₂ ); m / z (M ⁺ C ₂₃ H ₄₀ N ₄ O ₄ requires 436.30496) 436.30437.

Example 40 : (S) -3- (1 ', 1'-dimethylundecansulfonyl) aminocaprolactam

This compound is a sulfonamide analogue of Example 12.

Example 41: (S) -3- (2'-propylpentanoyl) aminocaprolactam :

(c = 1, CHCl₃) +29,4; n_max/см^-1 3303 (NH), 1686, 1633 (CO), 1537 (NH); d_H (500 МГц, CDCl₃) 6,88 (1H, д, J 5,5, CHNH), 6,52 (1H, шир.с, CH₂NH), 4,52 (1H, ддд, J 11, 6, 1,5, CHNH), 3,30-3,16 (2H, м, CH ₂NH), 2,13-2,02 (2H, м, (CH₂)₂CHCO и лактамное кольцо CH), 2,02-1,92 (1H, м, лактамное кольцо CH), 1,86-1,74 (2H, м, лактамное кольцо CH ×2), 1,57-1,50 (2H, м, боковая цепь CH₂), 1,42 (1H, шир.кд, J 13,5, 3,5, лактам кольцо CH), 1,38-1,29 (2H, м, лактамное кольцо CH + боковая цепь CH₂), 1,29-1,19 (4H, м, боковая цепь CH ×4), 0,85 (3H, т, J 7,5, CH₃) и 0,84 (3H, т, J 7,5, CH₃); d_C (125 МГц, CDCl₃) 175,8, 175,2 (CO), 51,9 (NHCHCO), 47,2 (CH), 42,1, 35,3, 35,1, 31,7, 28,9, 27,9, 20,7 (×2) (CH₂) и 14,1 (×2) (CH₃); m/z (МH⁺ C₁₄H₂₇N₂O₂ требует 255,2073) 255,2083.Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (15 ml) are added to a solution of 2-propylpentanoyl chloride (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture was stirred for 12 hours. Then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was recrystallized from hexane to give (S) -3- (2'-propylpentanoyl) aminocaprolactam (1.02 g; 80%); melting point (hexanes) 114-118 ° C;

(c = 1, CHCl ₃ ) +29.4; n _max / cm ^-1 3303 (NH), 1686, 1633 (CO), 1537 (NH); d _H (500 MHz, CDCl ₃ ) 6.88 (1H, d, J 5.5, CHN H ), 6.52 (1H, broad s, CH ₂ N H ), 4.52 (1H, ddd, J 11, 6, 1.5, C H NH), 3.30-3.16 (2H, m, C H ₂ NH), 2.13-2.02 (2H, m, (CH ₂ ) ₂ C H CO and lactam ring CH), 2.02-1.92 (1H, m, lactam ring CH), 1.86-1.74 (2H, m, lactam ring CH × 2), 1.57-1, 50 (2H, m, side chain CH ₂ ), 1.42 (1H, broad cd, J 13.5, 3.5, CH lactam ring), 1.38-1.29 (2H, m, lactam ring CH + side chain CH ₂ ), 1.29-1.19 (4H, m, side chain CH × 4), 0.85 (3H, t, J 7.5, CH ₃ ) and 0.84 (3H, t, J 7.5, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 175.8, 175.2 (CO), 51.9 (NH C HCO), 47.2 (CH), 42.1, 35.3, 35.1, 31, 7, 28.9, 27.9, 20.7 (× 2) (CH ₂ ) and 14.1 (× 2) (CH ₃ ); m / z (MH ⁺ C ₁₄ H ₂₇ N ₂ O ₂ requires 255.2073) 255.2083.

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

Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (15 ml) are added to a solution of (+/-) 2-ethylhexanoyl chloride (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture was stirred for 12 hours. Then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was recrystallized from hexane to give a mixture of (3S, 2'R) and (3S, 2'S) -3- (2'-ethylhexanoyl) aminocaprolactam (328 mg; 26%).

n _max / cm ^-1 3306 (NH), 1686, 1633 (CO), 1537 (NH); d _H (500 MHz, CDCl ₃ ) 6.89 (2H, d, J 5, CHN H , both isomers), 6.53 (2H, broad s, CH ₂ N H , both isomers), 4.52 ( 2H, ddd, J 11, 6, 1.5, C H NH, both isomers), 3.30-3.16 (4H, m, C H ₂ NH, both isomers), 2.06 (2H, broad. d, J 13.5, lactam CH × 2, both isomers), 2.02-1.92 (4H, m, (CH ₂ ) ₂ C H CO × 2 and lactam ring CH × 2, both isomers), 1 86-1.74 (4H, m, CH × 4 lactam ring, both isomers), 1.63-1.50 (4H, m, CH ₂ side chain), 1.50-1.30 (8H, m , CH × 4 lactam ring + CH ₂ × 4 side chain, both isomers), 1.30-1.14 (8H, m, CH ₂ × 8 side chain, both isomers), 0.85 (3H, t, J 7.5, CH ₃ , one isomer) and 0.82 (3H, t, J 7.5, CH ₃ , one isomer); d _C (125 MHz, CDCl ₃ ) 175.8, 175.1 (CO), 52.0, 51.9 (NH C HCO), 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 (CH ₃ ) and 12.0 (× 2) (CH ₃ ); m / z (M ⁺ C ₁₄ H ₂₆ N ₂ O ₂ requires 254.1994) 254.1995.

Example 43 : 3,3-dimethyldodecanoic acid (intermediate)

CuI (2 mmol), trimethylsilyl chloride (24 mmol) and methyl 3,3-dimethyl acrylate (20 mmol) in THF (25 mmol) are cooled to -15 ° C and nonylmagnesium bromide (24 mmol) in THF (80 ml). The reaction mixture was allowed to warm to room temperature overnight and then quenched by the addition of saturated aqueous ammonium chloride. THF was removed in vacuo and the residue was partitioned between hexanes and water. The organic layer was evaporated in vacuo and the crude methyl 3,3-dimethyldodecanoate was dissolved in ethanol (50 ml). KOH (100 mmol) in water (10 ml) was added and the reaction mixture was refluxed for 18 hours. The reaction mixture was then allowed to cool and the solvent was removed in vacuo, the residue was partitioned between hexane and water. Then, the aqueous layer was acidified to pH 2 with aqueous HCl and extracted with diethyl ether. The ether layer was dried over Na ₂ SO ₄ and the solution was then evaporated in vacuo to give 3,3-dimethyldodecanoic acid as an oil (3.47 g, 76%); n _max / cm ^-1 1702 (CO); d _H (500 MHz, CDCl ₃ ) 11.12 (1H, br s, OH), 2.21 (2H, s, CH ₂ CO); 1.32-1.20 (16H, m, (CH ₂ ) ₈ ), 1.00 (6H, s, C (CH ₃ ) ₂ ) and 0.87 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 179.1 (CO), 45.9, 42.3 (CH ₂ ), 33.2 ( C (CH ₃ ) ₂ ), 31.9, 30.3, 29, 6 (× 2), 29.3, 27.1 (× 2) (C ( C H ₃ ) ₂ ), 24.0, 22.6 (CH ₂ ) and 14.1 (CH ₃ ); m / z (M ⁺ C ₁₄ H ₂₈ O ₂ requires 228.2089) 228.2082.

Example 44 : 3,3-dimethyldodecanoyl chloride (intermediate)

3,3-Dimethyldodecanoic acid (5 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and oxalyl chloride (1 ml) and dimethylformamide (1 drop) were added. After 1 h, the reaction mixture was evaporated in vacuo to give crude 3,3-dimethyldodecanoyl chloride, which was directly used in the synthesis of (S) -3- (3 ', 3'-dimethyldodecanoyl) aminocaprolactam.

Example 45 : (S) -3- (3 ', 3'-dimethyldodecanoyl) aminocaprolactam:

(c = 1, CHCl₃) +28,6; n_max/см^-1 3279 (NH), 1646 (CO), 1498 (NH); d_H (500 МГц, CDCl₃) 6,81 (1H, д, J 5,5, CHNH), 6,59-6,42 (1H, шир.м, CH₂NH), 4,50 (1H, ддд, J 11, 6, 1,5, CHNH), 3,30-3,16 (2H, м, CH ₂NH), 2,08-2,02 (3H, м, CH₂CO + лактамное кольцо CH), 2,00-1,90 (1H, м, лактамное кольцо CH), 1,86-1,75 (2H, м, лактамное кольцо CH ×2), 1,47-1,31 (2H, шир.м, лактамное кольцо CH ×2), 1,30-1,17 (16H, м, (CH₂)₈), 0,89 (6H, с, C(CH₃)₂) и 0,84 (3H, т, J 7, CH₂CH ₃); d_C (125 МГц, CDCl₃) 175,8, 170,9 (CO), 52,0 (NHCH), 48,4, 42,6, 41,1 (CH₂), 33,3 (СМe₂), 31,9, 31,7, 30,4, 29,7, 29,6, 29,3, 28,9, 27,9 (CH₂), 27,3 (×2) (CH₃), 24,1, 22,6 (CH₂) и 14,1 (CH₃); m/z (М⁺ C₂₀H₃₈N₂O₂ требует 338,2933) 338,2928.Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam 2 (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (15 ml) are added to a solution of 3,3-dimethyldodecanoyl chloride (5 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture is stirred for 12 hours. Then the organic layer was separated and the aqueous phase was extracted further with dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was recrystallized from hexane to give (S) -3- (3 ', 3'-dimethyldodecanoyl) aminocaprolactam (1.14 g; 68%). Melting point (hexanes) 123-125 ° C;

(c = 1, CHCl ₃ ) +28.6; n _max / cm ^-1 3279 (NH), 1646 (CO), 1498 (NH); d _H (500 MHz, CDCl ₃ ) 6.81 (1H, d, J 5.5, CHN H ), 6.59-6.42 (1H, broad m, CH ₂ N H ), 4.50 ( 1H, ddd, J 11, 6, 1.5, C H NH), 3.30-3.16 (2H, m, C H ₂ NH), 2.08-2.02 (3H, m, CH ₂ CO + lactam ring CH), 2.00-1.90 (1H, m, lactam ring CH), 1.86-1.75 (2H, m, lactam ring CH × 2), 1.47-1.31 (2H, br.m, CH × 2 lactam ring), 1.30-1.17 (16H, m, (CH ₂ ) ₈ ), 0.89 (6H, s, C (CH ₃ ) ₂ ) and 0 84 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 175.8, 170.9 (CO), 52.0 (NH C H), 48.4, 42.6, 41.1 (CH ₂ ), 33.3 ( CM e ₂ ), 31.9, 31.7, 30.4, 29.7, 29.6, 29.3, 28.9, 27.9 (CH ₂ ), 27.3 (× 2) (CH ₃ ), 24.1, 22.6 (CH ₂ ) and 14.1 (CH ₃ ); m / z (M ⁺ C ₂₀ H ₃₈ N ₂ O ₂ requires 338.2933) 338.2928.

Example 46 : (E) -ethyl-2-methyldodec-2-enoate (intermediate)

Decanal (5 mmol) and (carbethoxyethylidene) triphenylphosphorane (10 mmol) were dissolved in CH ₂ Cl ₂ (20 ml) and the reaction mixture was stirred for 18 hours. Then the solvent was removed in vacuo and the residue was filtered through a plug of silica gel using 15% simple. diethyl ether in hexanes. The collected eluent was evaporated in vacuo to give (E) -ethyl-2-methyldodec-2-enoate as an oil (1.02 g, 88%); n _max / cm ^-1 1709 (CO), 1651 (C = C); d _H (500 MHz, CDCl ₃ ) 6.73 (1H, t, J 7.5, 1.5, CH = C), 4.16 (2H, q, J 7, OCH ₂ ), 2.13 ( 2H, brq, J 7.5, C H ₂ CH = C), 1.80 (3H, d, J 1.5, C H ₃ C = CH), 1.45-1.37 (2H, m, chain CH ₂ ), 1.32-1.19 (15H, m, (CH ₂ ) ₆ + OCH ₂ C H ₃ ) and 0.85 (3H, t, J 7, (CH ₂ ) ₈ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 168.3 (CO), 142.4 ( C H = C), 127.6 (CH = C ), 60.3 (OCH ₂ ), 31.8, 29.5 , 29.4 (× 2), 29.3, 28.6, 28.5, 22.6 (CH ₂ ), 14.3, 14.1 and 12.3 (CH ₃ );

m / z (MH ⁺ C ₁₅ H ₂₉ O ₂ requires 241.2168) 241.2165.

Example 47 : (E) -methyldodec-2-enoic acid (intermediate)

(E) -ethyl-2-methyldodec-2-enoate (1.43 mmol) was dissolved in ethanol (10 ml) and KOH (10 mmol) in water (5 ml) was added. The reaction mixture was refluxed for 18 hours and then cooled. The solvent was removed in vacuo and the residue was partitioned between water and hexane. The aqueous layer was acidified with aqueous HCl and extracted with diethyl ether. The diethyl ether layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give (E) -methyldodec-2-enoic acid as a solid (308 mg,>95%); melting point 28-31 ° C; d _H (400 MHz, CDCl ₃ ) 6.91 (1H, t, J 7.5, 1.5, CH = C), 2.18 (2H, broad k, J 7.5, C H ₂ CH = C), 1.82 (3H, d, J 1.5, C H ₃ C = CH), 1.48-1.39 (2H, m, CH ₂ chain), 1.36-1.19 ( 12H, m, (CH ₂ ) ₆ ) and 0.88 (3H, t, J 7, (CH ₂ ) ₈ C H ₃ ) (OH peak is not observed).

Example 48 : (E) -2-methyldodec-2-enoyl chloride (intermediate)

(E) -2-methyldodec-2-enoic acid (1.43 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and oxalyl chloride (1 ml) and dimethylformamide (1 drop) were added. After 1 hour, the reaction mixture was evaporated in vacuo to give crude (E) -2-methyldodec-2-enoyl chloride, which was directly used in the synthesis of (S) - (E) -3- (2'-methyldodec-2'-enoyl) aminocaprolactam .

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

(c = 1, CHCl₃) +38,2; d_H (500 МГц, CDCl₃) 7,15 (1H, д, J 5,5, NHCH), 6,48-6,35 (2H, м, NHCH₂ + CH=C), 4,54 (1H, ддд, J 11, 5,5, 1,5, NHCH), 3,33-3,17 (2H, м, CH ₂NH), 2,14-2,05 (3H, м, CH ₂CH=C + лактамное кольцо CH), 2,02-1,93 (1H, м, лактамное кольцо CH), 1,88-1,77 (5H, м, лактамное кольцо CH ×2 + CH ₃C=CH), 1,47-1,31 (4H, шир.м, лактамное кольцо CH ×2 + цепь CH₂), 1,31-1,17 (12H, м, (CH₂)₆) и 0,85 (3H, т, J 7, CH₂CH ₃); d_C (125 МГц, CDCl₃) 175,9, 168,2 (CO), 136,9 (CH=C), 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), 14,1 и 12,4 (CH₃).Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam 2 (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (15 ml) are added to a solution of (E) -2-methyldodec-2-enoyl chloride (1 , 43 mmol) in dichloromethane (15 ml) at ambient temperature and the reaction mixture was stirred for 12 hours. Then the organic layer was separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was recrystallized from hexane to give (S) - (E) -3- (2'-methyldodec-2'-enoyl) aminocaprolactam (297 mg; 65%). Melting point (hexanes) 99-100 ° C; n _max / cm ^-1 3282 (NH), 1656, 1622 (CO and C = C), 1497 (NH);

(c = 1, CHCl ₃ ) +38.2; d _H (500 MHz, CDCl ₃ ) 7.15 (1H, d, J 5.5, N H CH), 6.48-6.35 (2H, m, N H CH ₂ + CH = C), 4 54 (1H, ddd, J 11, 5.5, 1.5, NHC H ), 3.33-3.17 (2H, m, C H ₂ NH), 2.14-2.05 (3H, m, C H ₂ CH = C + lactam ring CH), 2.02-1.93 (1H, m, lactam ring CH), 1.88-1.77 (5H, m, lactam ring CH × 2 + C H ₃ C = CH), 1.47-1.31 (4H, broad m, CH × 2 lactam ring + CH ₂ chain), 1.31-1.17 (12H, m, (CH ₂ ) ₆ ) and 0.85 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 175.9, 168.2 (CO), 136.9 ( C H = C), 130.2 (CH = C ), 52.3 (NHCH), 42.2 ( NHCH ₂ ), 31.8, 31.6, 29.5, 29.4 (× 2), 29.3, 28.9, 28.7, 28.3, 27.9, 22.6 (CH ₂ ), 14.1 and 12.4 (CH ₃ ).

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

Example 50 (b) : (3S, 2'S) -3- (2'-methyldodecanoyl) aminocaprolactam;

(S) - (E) -3- (2'-methyldodec-2'-enoyl) aminocaprolactam (0.5 mmol) and Pd (OH) ₂ (20% on carbon) are added to methanol (10 ml) and the mixture is stirred for 18 hours at ambient temperature in a hydrogen atmosphere. The reaction mixture was then filtered and the solvent removed in vacuo to give (3S, 2'S) -3- (2'-methyldodecanoyl) aminocaprolactam as a solid (160 mg,>95%); n _max / cm ^-1 3313 (NH), 1671, 1636 (CO), 1515 (NH); d _H (500 MHz, CDCl ₃ ) 6.91 (2H, d, J 5.5, CHN H , both isomers), 6.55 (2H, broad s, CH ₂ N H , both isomers), 4, 57-4.47 (2H, m, C H NH, both isomers), 3.34-3.18 (4H, m, C H ₂ NH, both isomers), 2.29-2.14 (2H, CH ₃ C H CO, both isomers), 2.07 (2H, brd, J 13.5, CH lactam ring, both isomers), 2.02-1.94 (2H, m, CH lactam ring, both isomers ), 1.89-1.76 (4H, m, CH × 2 lactam ring, both isomers), 1.67-1.57 (2H, m, CH chain, both isomers), 1.51-1.33 (6H, m, CH × 2 lactam ring + CH ₂ side chain, both isomers), 1.32-1.18 (32H, m, (CH ₂ ) ₈ , both isomers), 1.13 (3H, d, J 7, CHC H ₃ , one isomer), 1.11 (3H, d, J 7, CHC H ₃ , one isomer) and 0.87 (6H, t, J 7.5, CH ₃ , both isomers); d _C (125 MHz, CDCl ₃ ) 175.9 (× 2), 175.8 (× 2) (CO, both isomers), 52.0, 51.9 (NCH), 42.1 (× 2) ( NCH ₂ , both isomers), 41.3, 41.2 ( C HCH ₃ ), 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) ( CH ₂ ) 17.8, 17.6 and 14.1 (× 2) (CH ₃ ); m / z (MH ⁺ C ₁₉ H ₃₇ N ₂ O ₂ requires 325.2855) 325.2858.

Example 51 : (4S, 2'S, 3'R) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one (intermediate)

This aldol reaction is carried out in accordance with a published method (Crimmins, MT; She, J .; Synlett, 2004, 1371-1374). (S) -4-benzyl-3-propionyloxazolidin-2-one (5 mmol) (synthesized according to the method of Evans et al. Tetrahedron Lett., 1987, 28, 1123) was dissolved in CH ₂ Cl ₂ (25 ml) and the solution was cooled to -20 ° C in an atmosphere of dry nitrogen and TiCl ₄ (5.25 mmol) was added. After 15 minutes, diisopropylethylamine (5.5 mmol) was added. After another 40 minutes, N-methylpyrrolidin-2-one (5.25 mmol) was added. After another 10 minutes, decanal (5.5 mmol) was added and the reaction mixture was stirred for 1 hour. A solution of ammonium chloride was added and the reaction mixture was washed with pH 2 buffer (0.5 M Na ₂ SO ₄ / 0.5 M NaHSO ₄ ). The organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product is chromatographed on silica gel (10% to 33% ethyl acetate in hexane) to give (4S, 2'S, 3'R) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) -oxazolidine-2- it is in the form of an oil (1.34 g, 69%); n _max / cm ^-1 1778 (NCO ₂ ), 1697 (CON); d _H (500 MHz, CDCl ₃ ) 7.35-7.30 (2H, m, meta-Ph ), 7.29-7.24 (1H, m, para- Ph), 7.21-7.17 (2H, m, ortho- Ph), 4.69 (1H, DDT, J 9.5, 7.5, 3.5, CHN), 4.21 (1H, t, J 9, OC H H), 4.17 (1H, dd, J 9, 3, OCH H ), 3.93 (1H, ddd, J 7, 4.5, 3, C H OH), 3.75 (1H, cd, J 7, 2.5, CHCH ₃ ), 3.24 (1H, dd, J 13.5, 3.5, C H HPh), 2.87 (1H, broad s, CHO H ), 2.78 (1H, dd, J 13.5, 9.5, CH H Ph), 1.56-1.20 (19H, m, (CH ₂ ) ₈ + CHC H ₃ ) and 0.86 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 177.6 (C C O), 153.0 (OCO), 135.0 ( ipso-Ph ), 129.4, 129.0 ( ortho - + meta - Ph), 127.4 ( pair -Ph), 71.5 (CHOH), 66.1 (OCH ₂ ), 55.1 (NCH), 42.1 ( C HCH ₃ ), 37.8, 33.8, 31, 9, 29.6 (× 3), 29.3, 26.0, 22.7 (CH ₂ ), 14.1 and 10.3 (CH ₃ ); m / z (MH ⁺ C ₂₃ H ₃₆ NO ₄ requires 390.2644) 390.2641.

Example 52 : (4R, 2'R, 3'S) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one (intermediate)

R-4-benzyl-3-propionyloxazolidin-2-one is converted to (4R, 2'R, 3'S) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one in accordance with the procedure described above. NMR spectroscopic data are identical; m / z (MH ⁺ C ₂₃ H ₃₆ NO ₄ requires 390.2644) 390.2638.

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

(4R, 2'S, 3'S) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one (1.42 mmol) was dissolved in THF (10 ml). Water (2 ml), aqueous hydrogen peroxide (8M, 0.5 mmol) and LiOH · H ₂ O (3 mmol) were added and the reaction mixture was stirred for 18 hours. Na ₂ SO ₃ (10 mmol) was added and the reaction mixture was extracted ethyl acetate. The aqueous layer was then acidified with buffer at pH 2 (0.5 M Na ₂ SO ₄ / 0.5 M NaHSO ₄ ) and extracted with diethyl ether. The diethyl ether layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give crude (2S, 3R) -3-hydroxy-2-methyldecanoic acid; d _H (400 MHz, CDCl ₃ ) 3.96-3.89 (1H, m, C H OH), 2.59 (1H, dc, J 7, 3, C H CH ₃ ), 1.54-1 36 (2H, m, CH ₂ ), 1.36-1.22 (14H, m, (CH ₂ ) ₇ ) and 1.20 (3H, d, J 7, CHC H ₃ ). This material is directly used in the synthesis of (3S, 2'S, 3'R) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam.

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

(2R, 3S) -3-hydroxy-2-methyldecanoic acid is obtained from (4R, 2'R, 3'S) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one according to with the procedure described above.

Example 55 : (3S, 2'S, 3'R) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam:

(c = 0,5, CHCl₃) +40,8; d_H (500 МГц, CDCl₃) 7,08 (1H, д J 5,5, NHCH), 6,51 (1H, шир.с, NHCH₂), 4,57 (1H, ддд, J 11, 6,5, 1, NCH), 3,83 (1H, дт, J 8, 4, CHOH), 3,36-3,21 (2H, м, NCH₂), 2,40 (1H, дк, J 7, 3, CHCH₃), 2,12-1,96 (2H, м, лактам CH ×2), 1,90-1,76 (2H, м, лактам CH ×2), 1,55-1,34 (4H, м, лактам CH ×2 + цепь CH₂), 1,34-1,21 (14H, м, (CH₂)₇), 1,17 (3H, д, J 7, CHCH ₃) и 0,88 (3H, т, J 7, CH₂CH ₃) (OH не наблюдается); d_C (125 МГц, CDCl₃) 175,8, 175,7 (CO), 72,1 (CHOH), 52,0 (NCH), 44,6 (CHCH₃), 42,1(2S, 3R) -3-hydroxy-2-methyldecanoic acid (1.40 mmol) was dissolved in MeOH (10 ml) and (S) -3-aminocaprolactamhydrochloride (1.50 mol) and triethylamine (2 mmol) were added. The reaction mixture was cooled to 0 ° C and 4- (4,6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride (1.40 mmol) was added. The reaction mixture was stirred for 4 hours and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with dilute aqueous HCl and dilute aqueous NaOH, and then dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was recrystallized from ethyl acetate / hexane to give (3S, 2'S, 3'R) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam as a solid (341 mg, 72%); melting point (hexanes) 88-91 ° C; n _max / cm ^-1 3313 (NH), 1628 (CO), 1480 (NH);

(c = 0.5, CHCl ₃ ) +40.8; d _H (500 MHz, CDCl ₃ ) 7.08 (1H, d J 5.5, N H CH), 6.51 (1H, br s, N H CH ₂ ), 4.57 (1H, ddd, J 11, 6.5, 1, NCH), 3.83 (1H, dt, J 8, 4, C H OH), 3.36-3.21 (2H, m, NCH ₂ ), 2.40 ( 1H, dc, J 7, 3, C H CH ₃ ), 2.12-1.96 (2H, m, lactam CH × 2), 1.90-1.76 (2H, m, lactam CH × 2) 1.55-1.34 (4H, m, lactam CH × 2 + chain CH ₂ ), 1.34-1.21 (14H, m, (CH ₂ ) ₇ ), 1.17 (3H, d, J 7, CHC H ₃ ) and 0.88 (3H, t, J 7, CH ₂ C H ₃ ) (OH not observed); d _C (125 MHz, CDCl ₃ ) 175.8, 175.7 (CO), 72.1 (CHOH), 52.0 (NCH), 44.6 ( C HCH ₃ ), 42.1

(NCH ₂ ), 33.4, 31.9, 31.3, 29.6 (× 2), 29.5, 29.3, 28.8, 27.9, 26.1, 22.7 (CH ₂ ), 14.1 and 11.2 (CH ₃ ); m / z (MH ⁺ C ₁₉ H ₃₇ N ₂ O ₃ requires 341.2804) 341.2776.

Example 56 : (3S, 2'R, 3'S) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam:

(c = 0,5, CHCl₃) +14,8; d_H (500 МГц, CDCl₃) 7,11 (1H, д, J 6, NHCH), 6,54 (1H, шир.с, NHCH₂), 4,53 (1H, ддд, J 11, 6,5, 1,5, NCH), 3,87-3,80 (1H, м, CHOH), 3,70 (1H, шир.с, OH), 3,34-3,20 (2H, м, NCH₂), 2,37 (1H, дк, J 7, 3, CHCH₃), 2,11-1,96 (2H, м, лактам CH ×2), 1,90-1,76 (2H, м, лактам CH ×2), 1,55-1,21 (18H, м, лактам CH ×2 + цепь (CH₂)₈), 1,16 (3H, д, J 7, CHCH ₃) и 0,88 (3H, т, J 7, CH₂CH ₃); d_C (125 МГц, 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), 14,1 и 10,7 (CH₃); m/z (МH⁺ C₁₉H₃₇N₂O₃ требует 341,2804) 341,2803.(2R, 3S) -3-hydroxy-2-methyldecanoic acid (1.40 mmol), (S) -3-aminocaprolactamhydrochloride (1.50 mmol), triethylamine (2 mmol) and 4- (4,6-dimethoxy) chloride [1,3,5] triazin-2-yl) -4-methylmorphorphinium (1.40 mmol) are reacted as described above to obtain (3S, 2'R, 3'S) -3- (3'-hydroxy-2 '-methyldecanoyl) aminocaprolactam, which is recrystallized from ethyl acetate / hexane (86 mg, 18%); melting point (hexanes) 118-121 ° C; n _max / cm ^-1 3294 (NH), 1667, 1613 (CO), 1533 (NH);

(c = 0.5, CHCl ₃ ) +14.8; d _H (500 MHz, CDCl ₃ ) 7.11 (1H, d, J 6, N H CH), 6.54 (1H, br s, N H CH ₂ ), 4.53 (1H, ddd, J 11, 6.5, 1.5, NCH), 3.87-3.80 (1H, m, C H OH), 3.70 (1H, br s, OH), 3.34-3.20 (2H, m, NCH ₂ ), 2.37 (1H, dc, J 7, 3, C H CH ₃ ), 2.11-1.96 (2H, m, lactam CH × 2), 1.90- 1.76 (2H, m, lactam CH × 2), 1.55-1.21 (18H, m, lactam CH × 2 + chain (CH ₂ ) ₈ ), 1.16 (3H, d, J 7, CHC H ₃ ) and 0.88 (3H, t, J 7, CH ₂ C H ₃ ); d _C (125 MHz, CDCl ₃ ) 175.9, 175.7 (CO), 72.0 (CHOH), 52.1 (NCH), 44.8 ( C HCH ₃ ), 42.1 (NCH ₂ ) , 33.7, 31.9, 31.4, 29.6 (× 2), 29.5, 29.3, 28.8, 27.9, 26.0, 22.7 (CH ₂ ), 14 1 and 10.7 (CH ₃ ); m / z (MH ⁺ C ₁₉ H ₃₇ N ₂ O ₃ requires 341.2804) 341.2803.

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

Butyllithium (2.5 M, in hexanes, 50 mmol) was 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 minutes and then methyl isobutyrate (50 mmol) was added. After 45 minutes, decanal (50 mmol) was added and the reaction mixture was allowed to warm to ambient temperature for 18 hours. After adding saturated aqueous ammonium chloride (10 ml), the reaction solvent was removed in vacuo and the residue was partitioned between hexanes and aqueous buffer at pH 2 (0.5 M NaHSO ₄ / 0.5 M Na ₂ SO ₄ ). The organic layer was dried over Na ₂ SO ₄ and the solvent was removed to obtain methyl 2,2-dimethyl-3-hydroxydecanoate as an oil (9.98 g, 77%); d _H (400 MHz, CDCl ₃ ) 3.70 (3H, s, OCH ₃ ), 3.69 (1H, dd, J 10, 2, C H OH), 1.68-1.20 (16H, m , (CH ₂ ) ₈ ), 1.19 (3H, s, CCH ₃ ), 1.17 (3H, s, CCH ₃ ) and 0.88 (3H, t, J 7, CH ₂ C H ₃ ) ( OH is not observed).

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

Methyl 2,2-dimethyl-3-hydroxydecanoate (20 mmol) was dissolved in EtOH (80 ml) and a solution of KOH (40 mmol) in water (20 ml) was added. The reaction mixture was refluxed for 18 hours and then the reaction mixture was allowed to cool. The solution was removed in vacuo and the residue was partitioned between water and diethyl ether. The aqueous layer was then acidified with buffer at pH 2 (0.5 M Na ₂ SO ₄ / 0.5 M NaHSO ₄ ) and extracted with diethyl ether. The solution was dried over Na ₂ CO ₄ and evaporated in vacuo to give 2,2-dimethyl-3-hydroxydecanoic acid, which solidifies upon standing; melting point 39-41 ° C; d _H (400 MHz, CDCl ₃ ) 3.64 (1H, dd, J 10, 2, C H OH), 1.67-1.12 (22H, m, (CH ₂ ) ₈ + C (CH ₃ ) ₂ ) and 0.88 (3H, t, J 7, CH ₂ C H ₃ ).

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

Example 59 (b) : (3S, 3'S) -3- (3'-hydroxy-2 ', 2'-dimethyldecanoyl) aminocaprolactam:

2,2-Dimethyl-3-hydroxydecanoic acid (1.77 mmol) and 1-hydroxybenzotriazole monohydrate (1.77 mmol) were dissolved in THF (10 ml). 1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.77 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 hours. A solution of hydropyrrolidine-5-carboxylate (S, S) -3- was added. aminocaprolactam 2 (2 mmol) and Na ₂ CO ₃ (6 mmol) in water (15 ml) and the reaction mixture was stirred for 18 hours. The reaction solvent was then removed in vacuo and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with buffer at pH 2 (0.5 M NaHSO ₄ / 0.5 M Na ₂ SO ₄ ) and dilute aqueous sodium hydroxide and then dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was chromatographed on silica gel (from 25% ethyl acetate in hexanes to 100% ethyl acetate) to obtain a mixture of (3S, 3'R) and (3S, 3'S) -3- (3'-hydroxy-2 ', 2'-dimethyldecanoyl) aminocaprolactam (557 mg, 88%); d _H (500 MHz, CDCl ₃ ) 7.28 (1H, d, J 6, N H CH one isomer), 7.25 (1H, d, J 6, N H CH, one isomer), 6.62- 6.48 (1H, br.m, N H CH ₂ , both isomers), 4.53-4.42 (1H, m, NCH, both isomers), 3.77 (1H, brd, J , 6 , OH, one isomer), 3.63 (1H, brd, J , 6, OH, one isomer), 3.47-3.36 (1H, m, C H OH, both isomers), 3.32 -3.17 (2H, m, NCH ₂ , both isomers), 2.07-1.92 (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 (CH ₂ ) ₈ + CH ₃ , both isomers), 1.14 (3H, s, CCH ₃ , both isomers) and 0.84 (3H, t, J 7, CH ₂ C H ₃ , both isomers); d _C (125 MHz, CDCl ₃ ) 177.6, 177.2, 175.8 (CO, both isomers), 77.8, 77.4 (CHOH), 52.1 (NCH, both isomers), 45, 9, 45.8 ( C (CH ₃ ) ₂ ), 42.1, 42.0 (NCH ₂ ), 31.9 (× 2) 31.6, 31.3, 30.9, 29.6 (× 4), 29.3, 28.8, 27.9, 26.7, 26.6, 22.6 (CH ₂ ), 23.7, 23.5, 21.1, 20.4 and 14.1 (CH ₃ ).

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

2,2-Dimethyl-3-hydroxypropionic acid (100 mmol) and 3,4-dihydro-2H-pyran (210 mmol) were dissolved in dichloromethane (50 ml) and para-toluenesulfonic acid (10 mg) was added and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction solvent is then removed and the residue dissolved in ethanol (100 ml). A solution of KOH (120 mmol) in water (30 ml) was added and the reaction mixture was refluxed for 18 hours. The reaction solvent was removed in vacuo and the residue was partitioned between water and diethyl ether. The aqueous layer was then acidified with buffer at pH 2 (0.5 M Na ₂ SO ₄ / 0.5 M NaHSO ₄ ) and then extracted with diethyl ether. The diethyl ether layer was then dried over Na ₂ SO ₄ and the solvent was removed in vacuo to give 2,2-dimethyl-3- (tetrahydropyran-2-yloxy) propionic acid as an oil (20.0 g,>95%); d _H (400 MHz, CDCl ₃ ) 4.62 (1H, t, J 3.5, CHO ₂ ), 3.82 (1H, ddd, J 12, 9, 3, CH ₂ O ring), 3.75 (1H, d, J 12, CH ₂ O chain), 3.55-3.46 (1H, m, CH ₂ O ring), 3.40 (1H, d, J 12, CH ₂ O chain), 1 90-1.45 (6H, m, (CH ₂ ) ₃ ), 1.25 (3H, s, CH ₃ ) and 1.23 (3H, s, CH ₃ ).

Example 61 : (S) - (2 ', 2'-dimethyl-3'-hydroxypropionyl) aminocaprolactam:

(c = 0,5, CHCl₃) +30,0; d_H (400 МГц, CDCl₃) 7,24 (1H, д, J 5,0, CHNH), 6,38 (1H, шир.с, CH₂NH), 4,49 (1H, дд, J 10, 6, CHNH), 3,54 (1H, д, J 11, CHHOH), 3,49 (1H, д, J 11, CHHOH), 3,33-3,20 (2H, м, CH ₂NH), 2,03-1,96 (2H, м, 2 × кольцо CH), 1,87-1,72 (2H, м, 2 × кольцо CH), 1,50-1,30 (2H, м, 2 × кольцо CH), 1,20 (3H, с, CH₃) и 1,18 (3H, с, CH₃); d_C (125 МГц, CDCl₃) 177,2, 176,0 (CO), 69,9 (CHOH), 52,1 (NHCHCO), 43,2 (CCO), 41,9 (CH₂N), 31,1, 28,8, 27,9 (CH₂ лактам), 22,4 и 22,3 (CH₃).2,2-dimethyl-3- (tetrahydropyran-2-yloxy) propionic acid (4.65 mmol), 1-hydroxybenzotriazole monohydrate (4.65 mmol) and carbonyldiimidazole (4.50 mmol) are dissolved in THF (30 ml) and the reaction the mixture was refluxed for 4 hours. After the reaction mixture was cooled to ambient temperature, a solution of hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam 2 (5 mmol) and Na ₂ CO ₃ (15 mmol) in water was added ( 30 ml) and the reaction mixture was stirred for 18 h. Then THF was removed from the reaction mixture by vacuum distillation and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was dissolved in MeOH and acetyl chloride (1 ml) was added. The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated in vacuo to give (S) - (2'2'-dimethyl-3'-hydroxypropionyl) aminocaprolactam as a solid (854 mg, 83%); melting point 97-99 ° C;

(c = 0.5, CHCl ₃ ) +30.0; d _H (400 MHz, CDCl ₃ ) 7.24 (1H, d, J 5.0, CHN H ), 6.38 (1H, broad s, CH ₂ N H ), 4.49 (1H, dd, J 10, 6, C H NH), 3.54 (1H, d, J 11, C H HOH), 3.49 (1H, d, J 11, C H HOH), 3.33-3.20 ( 2H, m, C H ₂ NH), 2.03-1.96 (2H, m, 2 × CH ring), 1.87-1.72 (2H, m, 2 × CH ring), 1.50- 1.30 (2H, m, 2 × CH ring), 1.20 (3H, s, CH ₃ ) and 1.18 (3H, s, CH ₃ ); d _C (125 MHz, CDCl ₃ ) 177.2, 176.0 (CO), 69.9 (CHOH), 52.1 (NH C HCO), 43.2 ( C CO), 41.9 (CH ₂ N), 31.1, 28.8, 27.9 (CH ₂ lactam), 22.4 and 22.3 (CH ₃ ).

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

(c = 0,5, CHCl₃) +16,4; d_H (500 МГц, CDCl₃) 7,33 (1H, д, J 5,0, CHNH), 6,82-6,62 (1H, шир.м, CH₂NH), 4,49 (1H, ддд, J 11, 5,5, 1,5, CHNH), 3,78 (1H, д, J 11, CHHCl), 3,74 (1H, д, J 11, CHHCl), 3,69 (1H, д, J 11, CHHCl), 3,66 (1H, д, J 11, CHHCl), 3,29-3,17 (2H, м, CH ₂NH), 2,05 (1H, шир.с, J 13,5, кольцо CH), 2,01-1,93 (1H, м, кольцо CH), 1,87-1,71 (2H, м, 2 × кольцо CH) и 1,49-1,31 (5H, м, 2 × кольцо CH + CH₃); d_C (125 МГц, CDCl₃) 175,4, 170,6 (CO), 52,6 (NHCHCO), 49,1 (CCO), 48,7, 48,6 (CH₂Cl), 42,1 (CH₂N), 31,1, 28,8, 27,9 (CH₂ лактам) и 18,9 (CH₃).Hydropyrrolidine-5-carboxylate (S, S) -3-aminocaprolactam 2 (5 mmol) and Na ₂ CO ₃ (15 mmol) in water (15 ml) are added to a solution of 3,3'-dichloropivaloyl chloride (5 mmol) in dichloromethane ( 15 ml) at ambient temperature and the reaction mixture was stirred for 12 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane (2 x 25 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by recrystallization from hexane to give (S) - (3'-chloro-2 '- (chloromethyl) -2'-methylpropionyl) aminocaprolactam (973 mg; 69%); melting point (hexanes) 95-96 ° C.

(c = 0.5, CHCl ₃ ) +16.4; d _H (500 MHz, CDCl ₃ ) 7.33 (1H, d, J 5.0, CHN H ), 6.82-6.62 (1H, broad m, CH ₂ N H ), 4.49 ( 1H, ddd, J 11, 5.5, 1.5, C H NH), 3.78 (1H, d, J 11, C H HCl), 3.74 (1H, d, J 11, C H HCl ), 3.69 (1H, d, J 11, C H HCl), 3.66 (1H, d, J 11, C H HCl), 3.29-3.17 (2H, m, C H ₂ NH ), 2.05 (1H, br s, J 13.5, CH ring), 2.01-1.93 (1H, m, CH ring), 1.87-1.71 (2H, m, 2 × CH ring) and 1.49-1.31 (5H, m, 2 × CH + CH ₃ ring); d _C (125 MHz, CDCl ₃ ) 175.4, 170.6 (CO), 52.6 (NH C HCO), 49.1 ( C CO), 48.7, 48.6 (CH ₂ Cl), 42.1 (CH ₂ N), 31.1, 28.8, 27.9 (CH ₂ lactam) and 18.9 (CH ₃ ).

Pharmacological study of the products of the invention

Inhibition of MCP-1-induced leukocyte migration

Principle of analysis

The biological activity of the compounds of the present invention can be demonstrated using any of a wide range of functional in vitro leukocyte migration assays, including, but not limited to, Boyden's chamber and related well migration assays, agarose migration assays, and direct imaging chambers such as Dunn's chambers.

For example, to demonstrate inhibition of leukocyte migration in response to chemokines (but not other chemoattractants), a 96-well microplate analysis system for neural migration from Neuroprobe (Gaithersburg, MD, USA) was used. Basically, this analysis consists of two chambers separated by a porous membrane. A chemoattractant is placed in the lower compartment, and cells are placed in the upper compartment. After incubation for some period at 37 ° C, the cells move towards the chemoattractant, and the number of cells in the lower compartment is proportional to the activity of the chemoattractant (relative to the series of controls).

This analysis can be used with a range of different leukocyte populations. For example, freshly prepared human peripheral blood leukocytes can be used. Alternatively, subpopulations of leukocytes, including polymorphonuclear cells or monocytes, can be obtained using methods well known to those skilled in the art, such as density gradient centrifugation or magnetic bead separation. Alternatively, immortal cell lines that have been widely accepted as human peripheral blood leukocyte models, including but not limited to THP-1 cells, as a model of monocytes, or Jurkat cells as a model of intact T cells, can be used.

Although a range of conditions is acceptable for analysis to demonstrate inhibition of chemokine-induced leukocyte migration, a specific example is provided here.

Material

Well migration analysis systems are manufactured by Neuroprobe, Gaithersburg, MD, USA.

The plates used are ChemoTx tablets (Neuroprobe 101-8) and 30 μl clear tablets (Neuroprobe MP-30).

Gey Balanced Saline is purchased from Sigma (Sigma G-9779).

Fatty acid-free BSA (bovine serum albumin) is purchased from Sigma (Sigma A-8806).

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

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

THP-1 cell lines (European Cell Culture Collection) are used as the white blood cell population.

Test report

The following procedure is used to test the compounds of the invention to detect leukocyte migration caused by MCP-1:

First, a cell suspension is obtained which is intended to be placed in the upper compartment. THP-1 cells are pelleted by centrifugation (770 x g; 4 min) and washed with balanced Geys saline with 1 mg / ml BSA (GBSS + BSA). Then this washing is repeated, and the cells are reprecipitated before resuspension in a small volume of GBSS + BSA for counting, for example, using a standard hemocytometer.

Then the volume of GBSS + BSA is adjusted depending on the number of cells present, so that the cells are present in a final area of 4.45 x 10 ⁶ cells per 1 ml of GBSS + BSA. This ensures that 100,000 THP-1 cells are present in every 25 μl of the solution, which should be placed in the upper chamber of the plate.

To test one compound for its ability to inhibit MCP-1-induced migration, it is necessary to obtain 2 lots of cells. A suspension of THP-1 cells at a concentration of 4.45 x 10 ⁶ cells / ml is divided into 2 vessels. The test inhibitor is added to a single vessel in an appropriate final concentration in an appropriate vehicle (e.g., in an amount of 1 μM in not more than 1% DMSO). A corresponding equal volume of GBSS + BSA plus carrier (eg, not more than 1% DMSO) is added to the second vessel to act as a control.

A chemoattractant solution is then prepared for placement in the lower compartment. MCP-1 was diluted in GBSS + BSA to obtain a final concentration of 25 ng / ml. This solution is divided into two vessels, as for cell suspension. The test compound is added to one vessel to the same final concentration as added to the cell suspension, while the corresponding equal volume of GBSS + BSA plus vehicle (eg, not more than 1% DMSO) is added to the other vessel.

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

After receiving chemoattractant solutions for the lower wells and cell solutions for the upper chambers, a migration chamber should be assembled. Pipette 29 μl of the appropriate chemoattractant solution into the lower well of the chamber. Analyzes should be performed with at least triplicate determinations of each condition. After filling all the lower chambers, apply a porous membrane to the chamber in accordance with the manufacturer's instructions. Finally, apply 25 μl of the appropriate cell solution to each upper chamber. To prevent evaporation, a plastic cover is placed on the entire device.

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

At the end of the incubation, the liquid cell suspension is carefully removed from the upper chamber and 20 μl of ice-cold 20 mM EDTA in PBS is added to the upper chamber and the device is incubated at 4 ° C for 15 minutes. This procedure causes any cells adhering to the lower side of the membrane to fall into the lower chamber. After this incubation, the filter is carefully rinsed with GBSS + BSA to wash the EDTA and then the filter is removed.

The number of cells migrated to the lower chamber in each condition can then be determined in a number of ways, including direct counting, labeling with fluorescent or radioactive markers, and using vital dye. Typically, applicants use MTT vital dye. 3 μl of MTT stock solution is added to each well and then the plate is incubated at 37 ° C for 1-2 hours, at which time the dehydrogenase enzymes inside the cells turn the soluble MTT into an insoluble product of blue formazan, which can be quantified spectrophotometrically.

In parallel, build an 8-point standard curve. Starting with the number of cells added to each upper chamber (100,000), and going down twice in serial dilutions in GBSS + BSA, the cells are added to a plate of 25 μl with the addition of 3 μl of MTT stock solution.

A standard curve plate is incubated along with plate migration.

At the end of this incubation, the liquid is carefully removed from the lower chambers, taking care to avoid disturbance of the precipitated formazan product. After allowing short-term air drying, 20 μl of DMSO was added to each lower chamber to dissolve the blue dye and the absorbance at 595 nm was determined using a 96-well plate reader. The spectral absorbance of each well is then interpolated onto a standard curve to estimate the number of cells in each lower chamber.

The stimulated migration of MCP-1 is determined by subtracting the average number of cells that reached the lower compartment in the wells where MCP-1 was not added from the average number of cells that reached the lower compartment where MCP-1 was present at a concentration of 25 ng / ml.

The exposure of the test substance is calculated by comparing the MCP-1-induced migration that occurred in the presence or absence of different concentrations of the test substance. Typically, migration inhibition is expressed as a percentage of the total MCP-1-induced migration that is blocked by the presence of the compound. For most compounds, a dose-response graph is constructed by determining the inhibition of MCP-1-induced migration that occurs in the range of different concentrations of the compound (usually in the range of 1 nM to 1 μM or higher for compounds with low activity). Then, the inhibitory activity of each compound is expressed as the concentration of the compound required to reduce the MCP-1 induced migration by 50% (ED ₅₀ concentration).

results

The compounds of Examples 1-7 and 9-34 and 39, 41, 42, 45, 49, 50, 55, 56, 61 and 62 were tested, and it was shown that in this test their ED ₅₀ was 100 nM or less.

Enantioselectivity

The (S) and (R) enantiomers of three different members of the aminocaprolactam series were synthesized to determine whether enantioselectivity was biologically active.

Comparison was made of compounds of examples 1 and 7, compounds of examples 10 and 11 and compounds of examples 12 and 17.

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

These data on three representatives of examples of the aminocaprolactam series demonstrate that, for the use of the compounds of the present invention, it is preferable to use the pure (S) -enantiomer of the compound rather than the racemic mixture of the two enantiomers or the pure (R) -enantiomer as anti-inflammatory agents in vivo.

In vivo activity of the compounds of the invention :

The anti-inflammatory activity of the compounds of the invention was determined in vivo using a sublethal endotoxemia model induced by LPS (lipopolysaccharide). Adult male CD-1 mice (n = 6 per group) were pretreated with various agents (vehicle, compounds of the invention or positive control agents, such as steroid decamethasone) by subcutaneous injection 30 minutes before an acute inflammatory challenge 750 μg bacterial lipopolysaccharide ( from E. Coli 0111: B4; Sigma catalog # L-4130) via the intraperitoneal route. The carrier in each case was 0.6% DMSO, 1% carboxymethyl cellulose, or alternatively 1% carboxymethyl cellulose. For some of the compounds, this composition results in a finely divided suspension or slurry, rather than a clear solution. 2 hours after the provocative test with LPS, the animals were killed and the blood was aspirated by cardiac puncture. The pro-inflammatory cytokine TNF-alpha level was determined using a Quantikine M ELISA (R&D Systems) for mouse TNF-alpha and the results were presented as mean ± standard error for each group.

Mice that did not receive the LPS challenge test had very low circulating levels of TNF-alpha (typically 10 pg / ml). By 2 hours after a provocative test with LPS, they increased more than 1000 times to an average level of 20,000 pg / ml, representing a sensitive indicator of inflammatory activation. Pretreatment with known anti-inflammatory drugs (such as the steroid dexamethasone) reduced TNF-alpha stimulation by up to 85-95%, depending on the dose administered.

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 to a similar extent with dexamethasone when a suitable dose was administered. All five compounds were maximally active at a dose below 1 mg / kg.

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

Claims (57)

1. Derived 3-aminocaprolactam of the formula (I)

where X represents —CO — R ¹ or —SO ₂ —R ² ,
R ¹ represents an alkyl (with the exception of 5-methylheptanyl and 6-methylheptanyl, where the radical R ^{1 is} attached to the carbonyl at position 1), haloalkyl, alkoxy (with the exception of tert-butyloxy), alkenyl, alkynyl or alkylamino radical of 4-20 atoms carbon (e.g., 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
R ² represents an alkyl radical of 4-20 carbon atoms (for example, of 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 atoms carbon, 14-18 carbon atoms, 13-17 carbon atoms);
or a pharmaceutically acceptable salt thereof. 2. The compound of formula (I ')

,
where X has the meaning defined in claim 1, or its pharmaceutically acceptable salt. 3. A pharmaceutical composition having anti-inflammatory activity, comprising, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof

where X represents —CO — R ¹ or —SO ₂ —R ² ,
R ¹ represents an alkyl (with the exception of 5-methylheptanyl and 6-methylheptanyl, where the radical R ^{1 is} attached to the carbonyl at position 1), haloalkyl, alkoxy (with the exception of tert-butyloxy), alkenyl, alkynyl or alkylamino radical of 4-20 atoms carbon (e.g., 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
R ² represents an alkyl radical of 4-20 carbon atoms (for example, of 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 atoms carbon, 14-18 carbon atoms, 13-17 carbon atoms);
and at least one pharmaceutically acceptable excipient and / or carrier. 4. A pharmaceutical composition having anti-inflammatory activity, comprising, as an active ingredient, a compound of formula (I ') or a pharmaceutically acceptable salt thereof

where X has the meaning defined in claim 3, and at least one pharmaceutically acceptable excipient and / or carrier. 5. The use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an inflammatory disorder

where X represents —CO — R ¹ or —SO ₂ —R ² ,
R ¹ represents an alkyl (with the exception of 5-methylheptanyl and 6-methylheptanyl, where the radical R ^{1 is} attached to the carbonyl at position 1), haloalkyl, alkoxy (with the exception of tert-butyloxy), alkenyl, alkynyl or alkylamino radical of 4-20 atoms carbon (e.g., 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
R ² represents an alkyl radical of 4-20 carbon atoms (for example, of 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 atoms carbon, 14-18 carbon atoms, 13-17 carbon atoms). 6. The use of a compound of general formula (I ′) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an inflammatory disorder

where X has the meaning defined in clause 5. 7. The compound according to claim 1, or its pharmaceutically acceptable salt, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is linear. 8. The compound according to claim 1, or its pharmaceutically acceptable salt, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is branched. 9. The compound according to claim 1, or its pharmaceutically acceptable salt, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is 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 R ¹ has alpha-carbon (position 2 in X), which is substituted by one or two identical or different groups selected from alkyl and halogenated radicals. 11. The compound of claim 10, where the radical R ¹ has alpha-carbon (position 2 in X), which is di-substituted by the same or different groups selected from alkyl and halogenated radicals. 12. The compound of claim 10 or 11, where the alpha carbon is chiral. 13. The compound of claim 12, wherein the alpha carbon has sp3 hybridized bonds. 14. The compound of claim 12, wherein the alpha carbon has substantially tetrahedral bond angles. 15. The composition according to claim 3, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is linear. 16. The composition according to claim 3, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is branched. 17. The composition according to claim 3, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is 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 R ¹ has alpha-carbon (position 2 in X), which is substituted by one or two identical or different groups selected from alkyl and halogenated alkyl radicals. 19. The composition according to p. 18, where the radical R ¹ has alpha carbon (position 2 in X), which is di-substituted by the same or different groups selected from alkyl and halogenated radicals. 20. The composition according to p. 18 or 19, where the alpha carbon is chiral. 21. The composition according to claim 20, where the alpha carbon has sp3 hybridized bonds. 22. The composition according to claim 20, where the alpha carbon has essentially tetrahedral bond angles. 23. The use according to claim 5, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is linear. 24. The use according to claim 5, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is branched. 25. The use according to claim 5, where the alkyl, halogenated, alkoxy, alkenyl, alkynyl or alkylamino part of the radical R ¹ is 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 R ¹ has alpha carbon (position 2 in X), which is substituted by one or two identical or different groups selected from alkyl and halogenated radicals. 27. The application of claim 26, wherein the R ¹ radical has alpha carbon (position 2 in X) that is di-substituted with the same or different groups selected from alkyl and haloalkyl radicals. 28. The use of claim 26 or 27, wherein the alpha carbon is chiral. 29. The application of claim 28, wherein the alpha carbon has sp3 hybridized bonds. 30. The application of claim 28, wherein the alpha carbon has substantially tetrahedral bond angles. 31. The compound according to claim 1, which is selected from the group consisting of:
(S) -3-hexadecanoylaminocaprolactam;
(S) -3-undecanoylaminocaprolactam;
(S) -3- (undec-10-enoyl) aminocaprolactam;
(S) -3- (undec-10-inoyl) aminocaprolactam;
(S) -3-dodecanoylaminocaprolactam;
(S) -3-tetradecanoylaminocaprolactam;
(R) -3-hexadecanoylaminocaprolactam;
(S) -3-okstadecanoylaminocaprolactam;
(S) - (Z) -3- (hexadec-9-enoyl) aminocaprolactam;
(S) - (Z) -3- (octadec-9-enoyl) aminocaprolactam;
(R) - (Z) -3- (octadec-9-enoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam;
(S) -3- (decyloxycarbonyl) aminocaprolactam;
(S) - (E) -3- (dodec-2-enoyl) aminocaprolactam;
(S) -3- (dec-9-enylaminocarbonyl) aminocaprolactam;
(S) -3- (decylaminocarbonyl) aminocaprolactam;
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-hexadecanoylaminocaprolactam;
(S) -3-undecanoylaminocaprolactam;
(S) -3- (undec-10-enoyl) aminocaprolactam;
(S) -3- (undec-10-inoyl) aminocaprolactam;
(S) -3-dodecanoylaminocaprolactam;
(S) -3-tetradecanoylaminocaprolactam;
(R) -3-hexadecanoylaminocaprolactam;
(S) -3-okstadecanoylaminocaprolactam;
(S) - (Z) -3- (hexadec-9-enoyl) aminocaprolactam;
(S) - (Z) -3- (octadec-9-enoyl) aminocaprolactam;
(R) - (Z) -3- (octadec-9-enoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam;
(S) -3- (decyloxycarbonyl) aminocaprolactam;
(S) - (E) -3- (dodec-2-enoyl) aminocaprolactam;
(S) -3- (dec-9-enylaminocarbonyl) aminocaprolactam;
(S) -3- (decylaminocarbonyl) aminocaprolactam;
and their pharmaceutically acceptable salts. 33. The use according to claim 5, where the compound is selected from the group consisting of:
(S) -3-hexadecanoylaminocaprolactam;
(S) -3-undecanoylaminocaprolactam;
(S) -3- (undec-10-enoyl) aminocaprolactam;
(S) -3- (undec-10-inoyl) aminocaprolactam;
(S) -3-dodecanoylaminocaprolactam;
(S) -3-tetradecanoylaminocaprolactam;
(R) -3-hexadecanoylaminocaprolactam;
(S) -3-okstadecanoylaminocaprolactam;
(S) - (Z) -3- (hexadec-9-enoyl) aminocaprolactam;
(S) - (Z) -3- (octadec-9-enoyl) aminocaprolactam;
(R) - (Z) -3- (octadec-9-enoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam;
(S) -3- (decyloxycarbonyl) aminocaprolactam;
(S) - (E) -3- (dodec-2-enoyl) aminocaprolactam;
(S) -3- (dec-9-enylaminocarbonyl) aminocaprolactam;
(S) -3- (decylaminocarbonyl) aminocaprolactam;
and their pharmaceutically acceptable salts. 34. The compound according to claim 1, which is selected from the group consisting of:
(R) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpentanoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpent-4-enoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylbutyryl) aminocaprolactam;
(S, E) -3- (2 ', 2'-dimethyldodec-4'-enoyl) aminocaprolactam;
(S) -3- (2 ', 2', 5'-trimethylhex-4'-enoyl) aminocaprolactam;
(S) -3- (2 ', 2', 5'-trimethylhexanoyl) aminocaprolactam;
(S) -3- (11'-bromundecanoyl) aminocaprolactam;
(S) -3- (11'-azidoundecanoyl) aminocaprolactam;
(S) sodium 3- (undecanoyl) aminocaprolactam-11'-sulfonate tetrahydrate;
(S) -3- (decansulfonyl) aminocaprolactam;
(S) -3- (dodecansulfonyl) aminocaprolactam;
(S) -3- (tetradecanesulfonyl) aminocaprolactam;
(S) -3- (hexadecane sulfonyl) aminocaprolactam;
(S) -3- (octadecanesulfonyl) aminocaprolactam;
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'-dimethyldodecanoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpentanoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpent-4-enoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylbutyryl) aminocaprolactam;
(S, E) -3- (2 ', 2'-dimethyldodec-4'-enoyl) aminocaprolactam;
(S) -3- (2 ', 2', 5'-trimethylhex-4'-enoyl) aminocaprolactam;
(S) -3- (2 ', 2', 5'-trimethylhexanoyl) aminocaprolactam;
(S) -3- (11'-bromundecanoyl) aminocaprolactam;
(S) -3- (11'-azidoundecanoyl) aminocaprolactam;
(S) sodium 3- (undecanoyl) aminocaprolactam-11'-sulfonate tetrahydrate;
(S) -3- (decansulfonyl) aminocaprolactam;
(S) -3- (dodecansulfonyl) aminocaprolactam;
(S) -3- (tetradecanesulfonyl) aminocaprolactam;
(S) -3- (hexadecane sulfonyl) aminocaprolactam;
(S) -3- (octadecanesulfonyl) aminocaprolactam;
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'-dimethyldodecanoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpentanoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpent-4-enoyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam;
(S) -3- (2 ', 2'-dimethylbutyryl) aminocaprolactam;
(S, E) -3- (2 ', 2'-dimethyldodec-4'-enoyl) aminocaprolactam;
(S) -3- (2 ', 2', 5'-trimethylhex-4'-enoyl) aminocaprolactam;
(S) -3- (2 ', 2', 5'-trimethylhexanoyl) aminocaprolactam;
(S) -3- (11'-bromundecanoyl) aminocaprolactam;
(S) -3- (11'-azidoundecanoyl) aminocaprolactam;
(S) sodium 3- (undecanoyl) aminocaprolactam-11'-sulfonate tetrahydrate;
(S) -3- (decansulfonyl) aminocaprolactam;
(S) -3- (dodecansulfonyl) aminocaprolactam;
(S) -3- (tetradecanesulfonyl) aminocaprolactam;
(S) -3- (hexadecane sulfonyl) aminocaprolactam;
(S) -3- (octadecanesulfonyl) aminocaprolactam;
and their pharmaceutically acceptable salts. 37. The compound according to claim 2, which is selected from the group consisting of: (S) -3-hexadecanoylaminocaprolactam; (S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam; (S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam; 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-hexadecanoylaminocaprolactam; (S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam; (S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam; and
their pharmaceutically acceptable salts. 39. The use according to claim 5, where the compound is selected from the group consisting of: (S) -3-hexadecanoylaminocaprolactam; (S) -3- (2 ', 2'-dimethyldodecanoyl) aminocaprolactam; (S) -3- (2 ', 2'-dimethylpropionyl) aminocaprolactam; 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'-propylpentanoyl) aminocaprolactam;
(3S, 2'R) and (3S, 2'S) -3- (2'-ethylhexanoyl) aminocaprolactam;
(S) -3- (3 ', 3'-dimethyldodecanoyl) aminocaprolactam;
(S) - (E) -3- (2'-methyldodec-2'-enoyl) aminocaprolactam;
(3S, 2'R) and (3S, 2'S) -3- (2'-methyldodecanoyl) aminocaprolactam;
(3S, 2'S, 3'R) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam;
(3S, 2'R, 3'S) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam;
(3S, 3'R) and (3S, 3'S) -3- (3'-hydroxy-2 ', 2'-dimethyldecanoyl) aminocaprolactam;
(S) - (2 ', 2'-dimethyl-3'-hydroxypropionyl) aminocaprolactam;
(S) - (3'-chloro-2 '- (chloromethyl) -2'-methylpropionyl) aminocaprolactam;
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'-propylpentanoyl) aminocaprolactam;
(3S, 2'R) and (3S, 2'S) -3- (2'-ethylhexanoyl) aminocaprolactam;
(S) -3- (3 ', 3'-dimethyldodecanoyl) aminocaprolactam;
(S) - (E) -3- (2'-methyldodec-2'-enoyl) aminocaprolactam;
(3S, 2'R) and (3S, 2'S) -3- (2'-methyldodecanoyl) aminocaprolactam;
(3S, 2'S, 3'R) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam;
(3S, 2'R, 3'S) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam;
(3S, 3'R) and (3S, 3'S) -3- (3'-hydroxy-2 ', 2'-dimethyldecanoyl) aminocaprolactam;
(S) - (2 ', 2'-dimethyl-3'-hydroxy-propionyl) aminocaprolactam;
(S) - (3'-chloro-2 '- (chloromethyl) -2'-methylpropionyl) aminocaprolactam;
their pharmaceutically acceptable salts. 42. The use according to claim 5, where the compound is selected from the group consisting of:
(S) -3- (2'-propylpentanoyl) aminocaprolactam;
(3S, 2'R) and (3S, 2'S) -3- (2'-ethylhexanoyl) aminocaprolactam;
(S) -3- (3 ', 3'-dimethyldodecanoyl) aminocaprolactam;
(S) - (E) -3- (2'-methyldodec-2'-enoyl) aminocaprolactam;
(3S, 2'R) and (3S, 2'S) -3- (2'-methyldodecanoyl) aminocaprolactam;
(3S, 2'S, 3'R) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam;
(3S, 2'R, 3'S) -3- (3'-hydroxy-2'-methyldecanoyl) aminocaprolactam;
(3S, 3'R) and (3S, 3'S) -3- (3'-hydroxy-2 ', 2'-dimethyldecanoyl) aminocaprolactam;
(S) - (2 ', 2'-dimethyl-3'-hydroxypropionyl) aminocaprolactam;
(S) - (3'-chloro-2 '- (chloromethyl) -2'-methylpropionyl) aminocaprolactam;
their pharmaceutically acceptable salts. 43. The use according to claim 5 or 6, wherein 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, organ transplant rejection and / or delayed graft or organ function, a disorder characterized by elevated levels of TNF-α, psoriasis, skin wounds, disorders caused by intracellular parasites, allergies, Alzheimer's disease caused by reverse antigen oh reaction suppressing an immune response, multiple sclerosis, amyotrophic lateral sclerosis, fibrosis, and formation of adhesions. 44. A method of treating, alleviating, or preventing the symptoms of an inflammatory disease (including an adverse inflammatory reaction to any agent) by administering to the patient an anti-inflammatory amount of a compound according to claim 1 or 2, a composition according to claim 3 or 4, or a drug according to claim 5 or 6. 45. The compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} not a linear alkyl group. 46. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a branched alkyl group. 47. The compound according to claim 1 or its pharmaceutically acceptable salt, where the substituent R ¹ does not represent an alkyl group. 48. The composition according to claim 3, where the substituent R ¹ does not represent a linear alkyl group. 49. The composition according to claim 3, where the substituent R ¹ represents a branched alkyl group. 50. The composition according to claim 3, where the substituent R ¹ does not represent an alkyl group. 51. The use according to claim 5, where the substituent R ¹ does not represent a linear alkyl group. 52. The composition according to claim 3, where the substituent R ¹ represents a branched alkyl group. 53. The use according to claim 5, where the substituent R ¹ does not represent an alkyl group. 54. A synthetic intermediate that can be used in the synthesis of compounds of general formula (I) or (I '), selected from the group consisting of:
(E) -methyl-2,2-dimethyldodec-4-enoate;
(E) -2,2-dimethyldodec-4-enoyl chloride;
2,2,5-trimethylhex-4-enoyl chloride;
3,3-dimethyldodecanoyl chloride;
(E) -2-methyldodec-2-enoyl chloride;
(4S, 2'S, 3'R) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one;
(4R, 2'R, 3'S) -4-benzyl-3- (3'-hydroxy-2'-methyldecanoyl) oxazolidin-2-one;
(2R, 3S) -3-hydroxy-2-methyldecanoic acid;
2,2-dimethyl-3- (tetrahydropyran-2-yloxy) propionic acid. 55. The compound according to claim 1, which is (S) -3- (1 ', 1'-dimethylundecansulfonyl) aminocaprolactam or a pharmaceutically acceptable salt thereof. 56. The pharmaceutical composition according to claim 3, where the compound is (S) -3- (1 ', 1'-dimethylundecansulfonyl) aminocaprolactam or a pharmaceutically acceptable salt thereof. 57. The use of claim 5, wherein the compound is (S) -3- (1 ', 1'-dimethylundecansulfonyl) aminocaprolactam or a pharmaceutically acceptable salt thereof.

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