MXPA96005426A - Derivatives of aminosulphonic acids, use of them in the synthesis of pseudopeptides and procedure for preparation - Google Patents
Derivatives of aminosulphonic acids, use of them in the synthesis of pseudopeptides and procedure for preparationInfo
- Publication number
- MXPA96005426A MXPA96005426A MXPA/A/1996/005426A MX9605426A MXPA96005426A MX PA96005426 A MXPA96005426 A MX PA96005426A MX 9605426 A MX9605426 A MX 9605426A MX PA96005426 A MXPA96005426 A MX PA96005426A
- Authority
- MX
- Mexico
- Prior art keywords
- pseudopeptides
- equal
- chosen
- amine
- group
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing Effects 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 title claims description 16
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- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 150000001412 amines Chemical class 0.000 claims abstract description 15
- 150000003839 salts Chemical group 0.000 claims abstract description 14
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000003277 amino group Chemical group 0.000 claims abstract description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
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- 239000011593 sulfur Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- OOQRRYDVICNJGC-MRVPVSSYSA-N tert-butyl N-[(2S)-1-hydroxy-3-methylbutan-2-yl]carbamate Chemical compound CC(C)[C@@H](CO)NC(=O)OC(C)(C)C OOQRRYDVICNJGC-MRVPVSSYSA-N 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
Abstract
The present invention relates to: gamma-amino-alpha, beta unsaturated sulfonic acid derivatives of the formula (I), wherein: R is selected from hydrogen, fragments corresponding to the side chains of natural amino acids, substituted or unsubstituted, linear alkyl chains , branched or cyclic, arylalkyl chains, aryl or heteroaromatic ps, Y denotes hydrogen, including the possible salt forms of the corresponding amine, or any protecting p commonly used for the protection of the amine p, X denotes Cl, OH, OCH2CH3, OCH3, ONBu4, NHCH2Ph, process for the preparation thereof and its use in the synthesis of pseudopeptides, characterized by the presence of at least one sulfonamide type conjugated to a double link
Description
DERIVATIVES OF AMINOSULPHONIC ACIDS, USE OF THEM IN THE SYNTHESIS OF PSEUDOPEPTIDES AND PROCEDURE FOR
ITS PREPARATION
BACKGROUND OF THE INVENTION
This invention relates to animosulfonic acid derivatives and the use thereof in the synthesis of pseudopeptides, characterized by the presence of at least one sulfonamide type bond, and having a potent pharmacological activity. This invention also relates to a process for the synthesis of such aminosulfonic acid derivatives, as well as their use in the synthesis of such pseudopeptides.
STATE OF THE PREVIOUS TECHNIQUE
As is known, peptides have been studied for a long time, since they are the transition term in the study of many complex substances such as proteins; in addition, the peptides as such are already extremely important compounds, being the mediators of biological systems and which have proven to be of great importance in physiological and medical sectors.
Thanks to their characteristics, peptides develop a basic biological role in nature, and in many cases they are drugs that are used in various pathological conditions. In this regard, many studies have been carried out since the 1950s to determine the structure of many biologically active peptides; The determination of the structures has allowed to establish the synthesis of the peptides under examination and therefore to study their potential therapeutic effects. In many cases, these studies have led to satisfactory results, and in the years when it was possible to determine the structure, and consequently, to synthesize many peptides and proteins that have a pharmacological activity. One of the most important results achieved in this field was the determination of total amino acid series and insulin synthesis; other studies with respect to, for example, glutathione, a tripeptide found in most living cells, alpha-corticotropin, which is composed of 39 amino acids and is a component of the adrenocorticotrophic hormone ACTH, and oxytoein, a nonapeptide , which is a hormone of the pituitary gland involved in the contractions of the uterus; the last peptide, after many studies, has been isolated, characterized and synthesized, as reported in V. du VIGNEAUD, C. RESSLER, J. M. SWAN, C. W. ROBERTS, P. G.
KATSOYANNIS, S. GORDON, J. Am. Chem. Soc. 75.4879 (1953). Thanks to such studies, this substance at present is a real drug, which is normally used during the supply to induce contractions. Of clinical interest is also an analogue of vasopressin, consisting of eight amino acids and synthesized by R. HUGUENIN et al., Helv. Chim. Acta 49,695 (1966) and I. VAVRA et al., Lancet 1,948 (1968), which proved to be a powerful and selective antidiuretic to be used in the treatment of diabetes insipidus. Other vasopressin analogue peptides have been sited, which have also shown antidiuretic activity and have proven useful in promoting an increase in blood pressure. As it is known, the structure of peptides is characterized by the presence of bonds, of amide, which are also indicated by the term of peptide bonds; such bonds have a major disadvantage of being easily hydrolysable by hydrolytic enzymes (protease), which recognize them. The above hydrolytic activity by the enzymes, causes the breakdown of the molecule into fragments of different lengths, generally destroying the pharmacological activity that characterizes the starting peptide. Therefore, it is evident that the use of peptides as drugs implies the serious disadvantage that in
In most cases, the molecule provided with pharmacological activity does not reach the target where said pharmacological activity must be activated, as fast as the circle enters, it is attacked by hydrolytic enzymes, and due to the hydrolysis of some peptide bonds that take place, it is reduced in many fragments almost always avoiding any pharmacological activity. In addition, the peptides generally show a low or nonexistent oral bioavailability, with administration problems. To remedy the above disadvantages, many suitable studies have been carried out to identify compounds having structures and characteristics similar to those of the peptides, in order to preserve the pharmacological activity, but characterized by one or more peptide bonds, responsible for the already described instability of the peptide molecules due to their degradation into small fragments, and they are replaced by bonds of a different type. For example, it has been described by REYNA J. SIMON et al., Of the Chiron Corp. [Proc. Nati Acad. Sci., USA, 89,9367 (1992)], the so-called "peptoides", compounds that contain in their structure the same side chains of those of the natural amino acids, but which come from the bond between several molecules of glycine N- replaced; as a consequence, they lack the amine bonds
Characteristics of the natural peptides, as shown in the following formulas, are resistant against enzymatic degradation and are potentially usable as "peptidomimetic" drugs.
oec oide peptide
Other methods used for the synthesis of "peptidomimetic" compounds use the so-called vinilog acids in the construction of the preset sequence; as reported, for example by C & EN, September 20, 1993, p. 34, the amino acid vinylog is a compound wherein an ethylene group (i.e. two carbon atoms bonded by a double bond) is inserted between the carbon atom in the alpha position and the carbonyl carbon atom of a conventional amino acid. An amino acid of vinylog (vinylogosine) is, for example, a component of a cyclic peptide, cycloteonamide, a thrombin inhibitor [SCHREIBER
S. L. et al. JACS 114.6570 (1992); SCHREIBER et al. JACS 115, 12619 (1993)]. The use of vinylog amino acids in the synthesis of peptidomimetics gives the obtained compounds special chemical and conformational characteristics that can induce, for example, a different and more marked pharmacological activity compared with the corresponding traditional peptides, but does not solve the problem before. mentioned hydrolysis of the peptide bond, which is present in the peptidomimetics thus obtained. Always with the purpose of remedying the aforementioned disadvantages, many research groups throughout the world have studied the possibility of replacing at least one amide bond within the peptide structure with bonds having similar characteristics, but which are no longer recognizable by the hydrolytic enzymes, trying in this way to make the molecule less sensitive to hydrolysis, while maintaining at the same time as unaltered as possible the sequence of natural amino acids constituting the peptide, in order to preserve its characteristic of pharmacological activity. This type of appearance is known as "isosteric substitution" of the peptide bond and consists, for example, of the substitution of said peptide bond (-CO-NH-) with
groups such as isomers of ketomethylene (-CO-CH2-), amines (-CH2-NH-), ethylene bonds (-CH = CH-), alpha-difluoroketone (CO-CF2-), cyclopropane isotherms and the like, [Angew. Chem. Int. Ed. Engl. 30, 1283-1301 (1991)]. The aforementioned aspect has made it possible to obtain "pseudopeptide" compounds that have a significantly higher biostability, although said substitutions of the amide bond have caused the pseudopeptides thus obtained to have problems in solubility and administration. A particular attempt at isothermal substitution is reported by DB SHERMAN, AF SPATOLA, J. Am. Chem. Soc. 112,433-441 (1990) who, to make such substitution, used a thioamide bond (-CS-NH-), the which differs from the peptide (-C0-NH-) due to the substitution of amide oxygen with sulfur; unfortunately, although the thioamides resemble the amides satisfactorily, the biological studies carried out on these pseudopeptides have shown that the biological behavior of the compounds containing thioamide bonds is unpredictable. Always, in the field of isosteric substitution of the peptide bond, the pseudopeptides have also been studied and characterized by the presence of at least one sulfonamide bond substituting for an amide bond
[MOREE, W. J. et al. Tetrahedron Letters 33,6389 (1992); KRICHELDORF, H. R. et al. Synthesis 43 (1976); LUISI, G. et
to the. Tetrahedron Letters 34, 2391 (1993)]; this change creates a substitute for the peptide bond, which turns out to be characterized by significant changes in polarity, hydrogen bond production capacity and the acid-base character of the molecule. In addition, the sulfonamide linkage exhibits a greater metabolic stability compared to the amide bond, and is structurally similar to the cerazole transition state involved in the enzymatic hydrolysis of the air binding, causing the pseudopeptides containing at least one sulfonamide bond becomes an interesting candidate in the development of enzyme inhibitors of new drugs [LEVENSON, CH et al. J. Med. Chem. 27.228 (1984); GUEGAN, R. et al. J. Med. Chem. 29,1152 (1986); MAZDIYASNI, H. et al. Tetrahedron Letters 34,435 (1993)]. To obtain pseudopeptides characterized by the presence of at least one sulfonamide bond, attempts have been made to use alpha-aminosulfonamides, which, however, are known to be unstable and to decompose immediately by fragmentation [FRANKEL, M. et al. Tetrahedron 9.289 (1960); GILMORE, W. F. et al. J. Org. Chem. 43.3335 (1978); MOE, G. R. et al. Tetrahedron Letters 22,537 (1981); GARRIGUES, B. et al. Synthesis 810 (1988); MERRICKS, D. et al. J. Chem. Soc., Perkin 1.2169 (1991)]. As an alternative, beta-amino-sulfonamides have been used,
which are stable compounds; however, the resulting pseudopeptides show a very high conformational flexibility, since the simple carbon-carbon bond
[-HNCHR-CH2S02-] thus introduced into the skeleton of the pseudopeptide induces in the molecule an increase in free degrees thanks to the possibility of turning around its axis, thus increasing the possible conformations. It is greatly emphasized that the pharmacological activity depends enormously on the state of conformation of the molecule that constitutes the active principle.
OBJECTS OF THE INVENTION
It is an object of this invention to make the derivative products of suitable aminosulfonic acids to be used in the synthesis of pseudopeptides provided with stable bonds to the enzymatic hydrolytic activity. A further object of this invention is to provide aminosulfonic acid derivative products suitable for use in the synthesis of pseudopeptides, such as having a pharmacological potential activity. Another object of this invention is to provide pseudopeptides that have a better bioavailability
compared with the corresponding peptide compounds, as well as chemical-physical characteristics more favorable for their use as enzymatic inhibitors. Still another object of this invention is to provide a process for the synthesis of aminosulfonic acid derivatives, such as making industrial realization and application easy and offering significant economic advantages. Another object of this invention is to carry out a process for the use of aminosulfonic acid derivatives in the synthesis of pseudopeptides comprising at least one sulfonamide bond.
DESCRIPTION OF THE INVENTION
These and other related objects and advantages which will be clearly assessed by the following description are achieved by means of suitable products to be used in the synthesis of pseudopeptides, which products, according to this invention, have the following general formula:
• H I ^ (I)
R is selected from: hydrogen, fragments corresponding to the side chains of natural amino acids and in particular proteinogenic amino acids, linear, branched or substituted or unsubstituted cyclic alkyl chains, arylalkyl chains, aryl and heteroaromatic groups; Y indicates hydrogen, including in this case, the possible salt forms of the corresponding amine, or any protective group commonly used for the protection of amine groups; X denotes Cl, OH, OCH2CH3, OCH3, ONBu4, NHCH2Ph, with the proviso that: when Y is chosen from PhCHoCO, (CH.). COCO and X is chosen from OCH-.CH3, ONBu4 or when Y is chosen as PhOC? ^ CC and X is chosen as OCH2CH3 or when Y is a salt form of the corresponding amine and X is chosen as OH, R is different from CH. More particularly, always according to this invention, R is chosen from the side chains included in the proteinogenic amino acids, the Y is equal to the protective group (CH3) 3C-OCO-, the X is equal to OR-, where R ^ ^ is chosen from -CH3 and CH2CH3, according to the following formula:
O { H_q, C-0- C- N- CH- CHirCH- 30x0 * 1 (* I) H I R
with the proviso that: when R-, is CH2CH3, R is different from CH3. Alpha-beta unsaturated sulfonates, namely ethyl sulfonates and t-butylammonium sulfonates where the protecting group of the amine is (CH3) 3COCO, PhCH2C0 or PhOCH2CO, obtained exclusively-lens of alanine derivatives described in
Bull.Soc.Chim.Fr (1990) 127, 835-842, (Carretero et al.) As intermediaries in the synthesis of alpha-beta epoxysulfonates, were tested as potential inhibitors of D, D-? Etid ===? bacterial As has been seen, they are derived according to the present invention having the formula (I), wherein R is selected from: hydrogen, fragments corresponding to the side chains of the natural amino acids and in particular the proteinogenic amino acids, alkyl chains linear, cyclic, substituted or unsubstituted, arylalkyl chains, aryl and heteroaromatic groups, and denotes hydrogen, including in this case, the possible salt forms of the corresponding amine, or any protecting group commonly used for the protection of amine groups, X denotes Cl, OH, OCH2CH3, 0CH3, 0NBu4, NHCH2Ph, or
Gamma-amino-alpha, beta-unsaturated sulfonic acid derivatives are used as synthons in the synthesis of pseudopeptides characterized by the presence of at least one sulfonamide bond conjugated to a double bond, for example according to the following formula:
where R2 is selected from hydrgene, fragments corresponding to the side chains of natural amino acids and in particular proteinogenic amino acids, linear, branched or substituted or unsubstituted cyclic alkyl chains, arylalkyl chains, aryl and heteroaromatic groups and may be identical to R. In particular, when Y equals the protective group (CH3) 3C-OCO-, the formula is as follows:
(III)
The pseudopeptide compounds obtained using the derivatives (I) have always proved to be in accordance with this invention less sensitive to the hydrolytic activity of the enzymes compared to the corresponding peptides, being characterized by the presence of at least one type linkage. sulfonamia, which, unlike the amide bond, rc undergoes hydrolysis by the proteolytic enzymes, for which I opposed it being a potential inhibitor of it. As a consequence, the sulfonamide pseudopeptide thus obtained is __á = t l ru the corresponding peptide, and thanks to its stability can more easily reach the target where it can exercise a possible pharmacological activity. The greater stability to the enzymatic hydrolysis can allow, in the case of a therapeutic use of the pseudopeptide sulfo__aida, the administration of a low dose, with advantages of general telegeneration. The presence of the double bond in the alpha-beta position according to this invention makes it possible to obtain pseudo-peptides of the suifonamide type which have a greatly increased structural rigidity compared with the analogous pseudopeptides comprising beta-amino, alpha-sulphonic units, which lead to the derived pseudopeptides, as it is said, at too high a conformational flexibility. The structural rigidity, characteristic of the sulfonamide pseudopeptides obtained using the
gamma-amino-alpha, beta-unsaturated sulfonic acid derivatives according to this invention, leads to a reduction in the possible conformation states assumed by the molecule; furthermore, it has been found that the structural rigidity lends some characteristics to the pseudopeptides of sulfonamide similar to those of the corresponding peptides, which are attributable, for example, to the possibility of the formation of intramolecular hydrogen bonds, ie bonds between the various parts that make up the molecule. For example, according to this invention, the derivative of the formula (I), wherein: X is chosen equal to Cl and is chosen equal to (CH 3) 3C-OCO-R is chosen equal to Me, is used for the preparation of c_r-_e = to (IV) that has the following formula:
• b í iv)
As shown, the compound (IV) in a solution of a suitable solvent, is characterized by the formation of a hydrogen bond between the carbonyl group indicated by "a" and the group -NH- indicated by "b" in the formula; the formation
of a hydrogen bond of the aforementioned type forces the above compound (IV) to assume a space arrangement corresponding to a cycle of 14 atoms, with relevant shaping constraints that result in a marked shaping rigidity. As is known, the characteristic conformations of the traditional peptide compounds are partially affected by the possibility of the formation of intramolecular hydrogen bonds; such hydrogen bonds limit the possible degrees of freedom of the molecule, resulting in a marked reduction in possible conformations. The use of gamma-amino-alpha, beta-unsaturated sulfonic acid derivatives according to this invention to obtain corresponding sulfonamide pseudopeptides, it also allows • obtaining potential drugs characterized by a satisfactory bioavailability and which are, as a consequence, easily administrable. Still in accordance with this invention, gamma-amino-alpha, beta-unsaturated sulfonic acid derivatives can also be functionalized to the double bond, according to known methods, for example one can obtain an epoxy group at the alpha-beta position, or a cyclopropane group, suitable in any case to provide the rigidity to the molecule. Functionalization of double
The linkage can be carried out either in the gamma-amino-alpha, beta-unsaturated sulfadic acid derivative of the general formula (I) and then use the derivative thus functionalized in the synthesis of the sulfonamide pseudopeptides, or directly in the characterized pseudopeptides by the presence of at least one sulfonamide bond and obtained in accordance with this invention. According to this invention, the process for the synthesis of the gamma-amino-alpha, beta-unsaturated sulfonic acid derivatives of the general formula (I,), consists of converting, according to known methods, the natural amino acids into alpha- aminoaldehydes, which in turn are converted to the derivatives (I) through the Witting-Horner reaction.Always agree, with the invention, the sulfonic acid derivatives gamma-amino-alpha, beta-unsaturated (I) can be advantageously obtained starting from the proteinogenic amino acids either in the (L) or in the (D) form, the proteinogenic amino acids have a high accessibility and are sold, for the most part, at low prices, which causes the preparation of the derivatives (I) that are easier and more economical, even in the indusl plan, always in accordance with this invention, the pseudopeptides characterized by the presence of at least one sulfonamide bond such as, for example, example, that of the
formula (III), are obtained by means of a process comprising, for example, the conversion of the gamma-amino-alpha, beta-unsaturated sulfonic ester (II), wherein R is chosen from the side chains comprised in the proteinogenic amino acids, Y equals the protective group (CH3) 3COCO-, X is equal to OR ^, where R- ^ is chosen from -CH3 and -CH2CH3, in a suiflated salt, which is then subjected to activation and coupled to a compound that it has a suitable reactive group, such as, for example, the same group of the formula (II), in which the amine group has previously been released. The product (III) thus obtained can be subjected to other treatments, which provide for example the possibility of an alternate release and activation of either the sulfonic group or the amine group and the coupling of the product (III) with itself product (III) with the same compound (II) previously released in a suitable position, thus performing a synthesis method of pseudopeptides of sulfonamide according to this invention of the iterative type, based on protection, release and coupling methods. Still according to this invention, the derivative (II) can be subjected to release alternatively with the sulfonic ester or the amine group and iteratively coupled with natural amino acids.
In addition, this process has proved to be especially suitable, since it maintains substantially unaltered the stereochemical characteristics of the initial products, thus allowing to perform the different stages of protection, release and activation described in a stereoconservative form. The sulfonamide pseudopeptides obtained through this process and according to the invention are optically pure, considering the instrumental limits of the experiments carried out to determine the purity.
EXAMPLE 1 According to this invention, the synthesis of the compound having the following formula: c
(V)
it is carried out as described in the foregoing, and was set forth by way of example and not limiting this invention. a) Preparation of N-BOC-Alaninol. A solution constituted by 1 g (0.0112 moles) of C. { S alaninol dissolved in 22 ml of methylene chloride is treated with 2.45 g (0.0112 mol) of (BOC) 20 at a temperature of 0 ° C under stirring at room temperature, the solvent
evaporate and the residue is dissolved in 20 ml of diethyl ether. The ether phase thus obtained is washed with a 0.5 M H3P04 solution and then treated with brine, then with a 1.0 M NaHCO3 solution, then again with brine. The organic phase is anhydrified over sodium sulfate, the solvent is evaporated at low pressure and 1.95 g (yield 59%) of? S / N-BOC-alaninol are obtained. 1 H NMR (200 MHz, ppm, CDCl 3): 1.15 (3H, d, J = 6.7 Hz); 1.46! 9E, s'; 2.1 (1H, broad *; 3.5 (1H, m); 3.65 (2H, m); 4.66
large) . b) Preparation of N-BOC-Alaninal. A solution consisting of 1.9 g (1.3 ml, 15 mmol) of oxalyl chloride in 12 ml of methylene chloride is treated under nitrogen at a temperature of -63 ° C with a seluent constituted per 1.58 g of dimethyl sulfoxide 11,435 ml, 20 mmol) in 6.1 ml of methylene chloride. To the resulting solution is then added, within a period of 30 minutes, a solution constituted by 1.75 g of (S) N-BOC-alaninol (10 mmol) is dissolved in 71.4 ml of methylene chloride. After 10 minutes, a solution of 4.07 g of triethylamine (5.61 ml, 40 moles) in 12.2 ml of methylene chloride is added to the reaction mixture; the addition is made in 20 minutes and a nebulosity of the reaction mixture is observed. The eluent of
TLC analysis, (hexane: ethyl acetate 1: 1 [v / v]) has shown that after 10 minutes at a temperature of -63 ° C the reaction is complete. The reaction is then interrupted by a slow addition of 8 ml of water, always maintaining the temperature at -63 ° C and the reaction mixture under vigorous stirring. Then, the mixture is quickly emptied into 12C ml of n-hexane and washed with 50 ml of a KHS04 solution obtained by diluting 13 ml of a saturated solution of KHSC4 with 40 ml of water. The aqueous phase is extracted with ethyl ether. The organic phases thus obtained are combined, washed with a saturated solution of NaHCC (2 × 45 m), with water (3 × 45 ml) and brine (2 × 45 ml) The organic phase thus obtained is anhydrified with sodium sulphate, the solvent is evaporated at low pressure and 1.6 g of (S) N-BOC-Ala (a.i.i) were retained (52% yield, 0.11 NMR, 200 MHz, ppm, CDCl3): 1.35 (3H, d, J). = 6.5 Hz), 1.46 (9H, e], 4.25 (1H, n_), - 5.1 (1H, broad), 9.57 (lH, s) c) Preparation of sulfonate alpha, beta-unsaturated ethyl ester (V) A solution of SC g of ethyl diethylphosphoryl-etansuifonate (EtO) 2PO-CE2S03Et (19.2 mmoles)
(prepared as described in CARRETERO J.C. et al., Tetrahedron 43.5125 [1987]) in 72.0 ml of THF is treated under
nitrogen at a temperature of -78 ° C with 13.12 ml (21.1 mmol) of a 1.6 M solution of n-BuLi in n-hexane. The mixture is maintained for 20 minutes under stirring at a temperature of -78 ° C, then 3.3 g (19.2 mmoles) of (S) N-BOC-Alaninal obtained as described under b) dissolved in 5.0 ml of THF are added. After 30 minutes, the reaction is stopped by treating the mixture with phosphate buffer, pH 7, and the aqueous phase is extracted with ethyl ether. The extracted organic phases are combined and analyzed over sodium sulfate and the solvent is evaporated at low pressure. The crude mixture thus obtained is purified by flash chromatography, using n-hexane: ethyl acetate 7: 3 (v / v) as the eluent mixture, and 4.18 g of sulfonate (V) was obtained (78% yield). ^ H-RM (2 _-- MHz, ppm, CDC13): 1.33 (3? ¿. Z = €, 5
Hz); 1.39 (3H, t, J = 7.2 Hz); 1.46 (9H, s); 4.18 12H, q, J = 7.2 Hz, J = 1, 61 Hz); 6.83 (1H, dd J = 15.10 Hz, J = 4.96 Hz), 13C-RKN (200 MKz, ppm, CDCl3); 14.65 (CH3); 15.56 (CH3); 28.13 L [CH 3: 3) 47, 14 (CHN); 66.85 (CH-,); 123.86 (CH =); 149.61 (CH =). p. f. = 69-71 ° C [a3 D = -18. 06 ° (C = 0.98, CHCI3)
EXAMPLE 2 Always according to this invention, the compound having the following formula:
(SAW)
it is synthesized as described in the following, always by way of non-limiting example of this invention. to} Preparation of N-BOC-Val ± tel. Starting from (S) Valinol and following the procedure described by Example 1, point a), (S) N-BOC-Valinoi was obtained in 97% yields. -H-NMR (200 MHz, ppm, CDCl 3): 0.93 (3H, d, J = 6.7
__z '; C, S € v3 ?, d, J = 6, 7 Hz); 1.46 .9E, s}; 1.85 (lE, _-> 2.35! .__ am l "; 3.45 '1H, m); 3.66 (2 ?, __'; 4.65 '1H, broad.) B) Preparation of N -BOC-Valinal Starting from (S) N-BOC-Valinol and following the procedure described in Example 1, point b), we obtained: • S-50Z-V = l ____ al in yields of SZ-%. H-NMR (200 MHz, ppm, CDCl 3): 0.95 (3H, d, J = 6.5 Hz ^, 1.05 '3H, d, J = 6.5 Hz); 1.45 (9H, s), (9H, s), 2.30 'lE, m), 4.25 l =,), 5.22 (1H, broad), 9.65 (1H, s) c) Preparation of sulfonate ethyl aifa, beta-unsaturated (VI).
Starting from (S) N-BOC-Valinal and following the procedure described in Example 1, item c), the sulfonate of the formula (VI) was obtained in 77% yields. iH-NMR (200 MHz, ppm, CDC13): 1.96 (3H, d, J = 6.4 Hz); 0.98 (3H, d, J = 6.4 Hz); 1.39 (3H, t, J = 7.5 Hz); 1.47
(9H, s); 1.92 (lH, m, J = 6.4 Hz); 4.27 (2H, q, J = 7.5 Hz); 4.15 ilH,); 4.6; 1H, broad;; 6.32 UH, dd, J = 14.90 Hz, J = i, S3
Hz); 6.82 (1H, dd, J = 14.90 Hz, J = 4.80 Hz). 13 C-NMR (200 MHz, ppm, CDCl 3): 14.69 (CH_); 17.35? 2xC? 3-; 15.74, C? 3; 25,14 ^ C? -j ^;; 31.76. { And iK = 2 ~ - < 5 £, 3 AND ICHN); 66.81 (CK2 /; 125.16 (CH =); 147.63 (CH =). P.f. = 53-55 ° C [a] D = + 3.15 ° (c = 1.0, CHC13)
Always in accordance with this invention, the corpuuest has the following formula:
is prepared as described in the following, always by way of non-limiting example of this invention.
The procedure described in Example 1, points a), b) and c) is still starting from (S) alaninol, but methyl diethylphosphoryl-methanephosphonate (EtO) 2P0-CH2S03Me was used in place of ethyl diethylphosphoryl-methansulfonate ( EtO) 2PO-CH2S03Et. The crude mixture is purified by flash chromatography, using n-hexane: ethyl acetate: 25, v, -v as the eluent mixture and crystallized (n-hexane / ethyl acetate 7/3); methyl sulfonate alf-beta-p. f. = 63-51 = C
iH-NMR (200 MHz, ppm, CDCl 3): 1.33 (3H, d, J = 7.0 Hz); 1.45 (9H, s); 3.82 (3H, s); 4.45 (1H, m); 4.61 (lH, d, "= 4.43 Ez '; €. 2 ~ 1 ?,? ±. _ _. = .1C Hz, J = l, 60 Hz.; £, E_ l =
13 C-NMR (200 MHz, ppm, CDCl 3): 19.61 (CH 3); 28.15 (ECH3! 3; 46.75 (CHS); 56.16 (OCH3): 19.61 (C = ^; 25.15, ([CH3] -,; 46.75 CHN); 56.16 (OCH3); 122.71 (C? = 5; 150.66 (C? =).
EXAMPLE 6 (S) H-BOC-Prolinol. Following the previous process, the desired alcohol was obtained in a yield of 98%.
iH-NMR (d, CDCl3): 1.49 (9H, S, [CH3] 3C); 1.7-1.9, 2H,, NCHCH2CH2); 3.6 (2H, m, CH2OH); 3.95 (1H, m, NCH)); 4.78 (1H, broad, OH). (S) N-BOC-Prolinal. Following the previous procedure, (S) N-BOC-Prolinal was obtained in a yield of 96%. ^ E-NMR (d, CDCi3;: 1.45, 3E, s, [CH3] 3C); 1.75-2.3 = (4H, m, NCHCH2CH2); 3.43 (2H,, 3H2NCH); 4.1 (1H, broad,, NCg); 5-43 (1H, s, CHO). Following the procedure described in ic anterter, a crude mixture was obtained, which is purified by means of flash chromatography (n-hexar.o / AcOEt = 6/4) to give the desired sulfonate (XX) in a yield of 60% . [c_] D = -6.56 ° (c = 1.01, CHCI3). -? - 3ZS < d, -_rl3: 1.44 ==, e, [CH ^] 3C); 1.76-1.55
(3E, m, NC? CHH? I; 2.2 H, m, NCECHH); 3.43
m, NCHCH2CH2CH2); 3.81 (3H, S, OCH3); 4.5 (1H, m, NCH); 6.186 (1H, dd, CH = CHS03, J = 15.C7 Ez, = C93 Hz); 6.8 (1H, dd, CH = CHS03, J = 15.06 Hz, J = 5.67 Hz.) .15C-NMR (d, CDCl3): 20.905 (CH2); 28.222 ([CH3] .-);
31. 430 (CH2); 46.309 (CH2); 55,052 (CH); 57,083 (OCH3); 123.127 (CH =); 149.312 (CH =).
Likewise, sulfonate (XXI) has been prepared, which was obtained as a crude mixture and purified by means of flash chromatography (n-hexane / AcOEt = 90/10) to give the desired product with a yield of 46%.
BOC-NH - H-CH-CH -SO »OCHOCH_ CHjOSaBuPhj
1E-NMR (d, CDC13): 1.08 (9H, s, [CH3J3CSi); 1.36
(3H, t, OCH2CH3, J = 7.1 Hz); 1.47 (9H, s, [CH3] 3CO); 3.79 (2H, m, OCH2CH); 4.17 (2H, q, OCH2CH3, J = 7.1 Hz); 4.45 (1H, m,; 4.56, HI, d, NH, J = 6.3 Ez; £ .33 [l =, rr, E = IESO-, J = 1.6 Ez, J = 15.1 Hz); 6.9 (1H, dd, CE = CES03, J = 4.7 Kz, J = 15.1
Hz); 7.3-7.7 (10 H, m, 2 x PhSi). 13 C-NMR (d, DEPT, CDCl 3): 14,728 (OCH 2 CH 3); 26,751 (
; 28.174 ([CH3CO); 52,621 (CH.); 64,707 (CHCH20. '; 66,835 (OCH2CH3); 125,754 (CH = CHS); 127,886 (CH =); 130,024 (CH =); 135,455 (CH =); 146,623 (CH = CHS). Always following the procedure described, the sulfonate (XXII) was obtained as an exudate mixture and purified by means of flash chromatography (n-
hexane / AcOEt = 65/35) to give the desired product in a 56% yield.
BOC-NH -CH- CH-CH-SOrOCHjCH, ?? Ca-ljCHjCONHCPh,
1H-NMR (d, CDCi3J: 1.37 (3H, t, [CH3CH20, J = 7. i Hz); 1.44 (9H, s, [CH313C); 1.82-1.94 (2H, m, CH2CH2CO); 2.41
(2H, t, CH2CH2CO, J = 6.69 Hzl, 4.155 (2H, q, OCH2CH3, J = 7.1
Hz); 4.31 '1E, ~, NHZE; = .1? 1H, d, NHCE, = 5.6 Hz); 6.25
(1H, d, CH = CHS03, J = 15.19 Hz); 6.75 (2H, dd, CM = CHS03 +
NHCPh3, J = 5.25 Hz, J = 15.2 Ez); 7.18-7.32 (15H, m, ArH). 13 C-NMR (d, DEPT, CDCl 3): 14,702 (CH 3); 28,195
([CH3] 3); 29,582 (CH2); 33,072 (CH2); 56,762 (CHN); 66,986
(OCH2); 124,566 '==; 126.5.52 (CH =); 127.533 ÍCH =); 128,534
EXAMPLE 4 The process described in the above, which allows obtaining pseudopeptides characterized by the presence of at least one sulfonamide bond according to this invention, can be schematized as follows when, for example, the product (V) is used as an initial material:
SCHEME 1
I ») < V «>
(H CWC-O-S- M-CH- M-USM-tOaOCHaCHi H ^ M * - CH- CH = CH- aOtOCHjCM, CH, CM »O (« >
or II (HjCWC-O- C-> l- -CH-CH = -CH- SOftt CM- CH = CH-SOlOCHICHj H I M I
CH_ CM, l »»
and is described in detail in the examples given in the following. a) Preparation of the sulfonate salt (VIII).
A solution of 1.0 g (3.6 mmoles) of alpha, beta-unsaturated ethyl sulfonate (V) in 20 ml of acetone is treated, under a nitrogen atmosphere and under stirring, with 1.33 g.
(3.6 mmol) of n-Bu4NI recrystallized by means of a mixture of ethyl acetate / methanol 95/5. A reflux of the reaction mixture is allowed for 16 hours, inspecting by means of the progressive disappearance of TLC of the initial product, using n-hexane: ethyl acetate 6: 4 IV / VJ as the eluent system. After evaporation to na; under pressure of the solvent, 1774 g of the sulfonate salt (VIII) were obtained (100% yield). l-H-NMR (200 MHz, ppm, CDC13): 1.0 (12H, t, J = 7.6 Hz); 1.20 (3H, d, J = 6.8 Hz); 1.40 (9H, s); 1.4-1.8 (16H,? _; 3.3 (8H, m), 4.33 1E,! _; 4 45 LE, broad); 6.42 • 2H, m,. b) Preparation of amine hydrochloride (IX). 250 mg (0.89 mmcies) of alpha, beta-unsaturated ethyl sulfonate (V) were treated with 5 ml of a 3M HCl solution in methyl alcohol, under a nitrogen atmosphere and at a temperature of ° C. The reaction mixture is kept under stirring at ° C for 5 hours, inspecting by means of the progressive disappearance TLC of the initial product, using n-hexane: ethyl acetate 6: 4 (v / v) as the eluent system. The solvent then evaporates at low
pressure and the resulting product is placed under vacuum
(0.1 mmHg). 192 mg (100% yield) of the hydrochloride sai was obtained, which is used in the subsequent reactions without further purification. c) Preparation of pseudopeptides of sulfonamide vAl,. 180 ms (C.107 ml, 1.33 moles) of sulfeple chloride are added to a solution of 320 mg of triphenylphosphine Fn3F
'1 224 símeles > in 1.5 ml of methylene chloride at 0 °, under t-thi-er: the presence of re? Á molecular sieves.
Enterees is added under stirring a solution of 332 mg
(0.611 mrncies'i of the sulfonate salt (VIII) in 2.C ml of methylene chloride, at room temperature and under nitrogen.The reaction mixture is kept under stirring at room temperature for 150 minutes, then the
The solvent was removed at low pressure and the product was cross-purified by means of flash chromatography, using n-hexane: ethyl acetate 6: 4 (v / v) as eluent mixture. L42 g of sulfonyl chloride (X) yield of 6 is obtained. iH-NMR (PPM, 200 MHz, CDC13): 1.32 (3H, d, J = 7, 1 H-f; 1.42 '5E, s); 4.5 (1E, broad); 5.0 (1H, broad); 6, dC, L ?, dr, = 14, B0 Hz, J = l, 05? Z); 6.97 (1H, dd, J = 14.53 Hz J = 4.40 Hz).
13 C NM (ppm, MHz, CDCl 3): 19,364 (CH 3); 28.144 ([CH3] 3); 46,488 (CHN); 132,678 (CH =); 150.425 (CH =); 154,648 (C = 0). 142 mg (0.525 mmol) of sulfonyl chloride (X) obtained as described above are dissolved in 4.0 ml of methylene chloride and then a solution, all at once, consisting of 74.6 mg (0.35 mmole) is added. of (IX) in 2.0 ml of methylene chloride, comprising 0.352 ml (0.35 moles) of DBU and 5.4 mg (0.070 mmolee) of 4-rir.et laminopyridine .ZTK? -? -. After the addition, 0.078 ml is added
(3.525 mmoles) DBü in 1.0 ml of methylene chloride, slowly and over a period of three hours. A reflux of a mixture is left for 5 hours, then the mixture is diluted with chlorure re netllene and treated with 2.3 ml of pE 7 phosphate buffer. The aqueous phase is extracted with methylene chloride, the organic extracts are combined, Anhydrify on sodium sulfate and evaporate. A crude product was obtained, which is purified by means of flash chromatography, using a mixture of n-hexane: ethyl acetate 1: 1 (v / v) as eluent, obtaining
• XI} with 50% yields. iH-NMR (200, MHz, ppm, CDC13): 1.32 (3H, d, J = 7.1
Hz); 1.39 (3H, d, J = 7.0 Hz); 1.41 (3H, t, J = 7.0 Hz); 1.46 (9H, s); 4.15 (1H, m); 4.22 (2H, q, J = 7.0 Hz); 4.36 (1H, m);
4.75 (2H, m); 6.30 (1H, dd, J = 15.0 Hz, J = 1, 2 Hz); 6.47 (1H, dd, J = 15, 1, J = 1, 3 Hz); 6.68 (1H, dd, J = 15.0 Hz, J = 5.4 Hz); 6.82 (1H, dd, J = 15, l J = 5.2 HZ). 13 C-NMR (200 MHz, ppm, CDC13): 15.51 (CH 3); 20.30 (CH3); 21.51 (CH3); 28.91 [(CH313); 47.4 (CH); 50.23 (CH); 50.23 (CH); 67.91 (OCH2); 126.26 (CH =); 128.61 (CH =); 147.47 (CH =); 148.73 (CH =); 157 (0-C = 0).
EXAMPLE 5 Always according to this invention, the compound
(XII) which has the following formula:
< WI)
was prepared according to the methods already described in Examples 4, 5 and 6, starting with the compound (V) and the compound (VI); the compound (XII) was obtained in crude form and purified and characterized as described in the following. The crude product (XII) is purified by means of flash chromatography, using a mixture of n-hexane: ethyl acetate 6: 4 (v / v).
-H-NMR (200 MHz, ppm, CDC13): 0.98 (3H, d, J = 6.8 Hz) 0.99 (3H, d, J = 6.8 Hz); 1.30 (3H, d, J = 7, 1 Hz); 1.41 (3H, t, J = 7, 1 Hz); 1.45 (9H, s); 1.94 (1H, m); 3.86 (1H, m); 4.23
(2H, q, J = 7.1 Hz); 4.39 (1H, m); 4.75 (2H, m); 6.29 (1H, dd, J = 15, l Hz, J = l, 4Hz); 6.47 (1H, dd, J = 15.2 Hz, J = 1, 2 Hz, 6.68
(1H, dd J = 15, l Hz, J = 5.3 Hz;; 6.80 (1H, dd J = 15, l Hz, J = 5.3
13C-NMR 200, MHz, ppm, CDC13): 14.80 CH3); 18.04 'CE3); 18.59 (CE: 27.57 CE-; 25.21 ([CH-,] ..}.; 32.28 (CH); _.?L (CHN.).; 56, L5 2___7 - - ~ ZZ = 2 ', 126, 5L, I ==., L27.69 lCH =), 146.22 (CH =), L46, £ ~ LE =.
EXAMPLE 7
BOC -NH-CH-CH_a4-SQ * -CH-CH-CH-S - ^^ CHjPh H * Pr 0OC__?
To the product (I) where: Y = BOC, R = CH2Ph, X = C1 181.5 mg, 0.525 r_r: cles, er C 2IÍ2 (4 ml), a solution of (XII) is added as amine cyclamate
mg, 0.35 mmol) in CH2C12 (1 mL), containing DBU (0.052 mL, 0.35 mmol) and DMAP (8.4 mg, 0.070 mmol). Then add more DBU (0.078 mi, 0.525 mmoies) in CH-, Ci2 (1 role) and more suifoniio chloride ^ 60.5 mg, 0.175 mmoles; After 5 hours, the reaction mixture is diluted with CH-.C1-. and phosphate buffer (2 ml) is added. The aqueous phase is
extract with CH2C12 and collect and dry, the organic extracts are evaporated, to give a crude mixture which is purified by means of flash chromatography (n-hexane / AcOEt = 55/45) to give the product (XXIII) in a 60% yield. iH-NMR (500 MHz, d, CDCl 3): 0.95 (3H, d, CH 3 CHC, J = 7.5 Hz); 0.97 (3H, a, CE ^ CEC, J = 7.0 Hz); 1.31 (3H, d, CH3CHN, J = 6.5 Hz); 1.38 (9H, s, [CH_3] 3C); 1.40 (3H, t, CH-'CE20S02, J = 7.0 Ez.); 1.85 'LE,, Me2CHC); 2.82 (1H, dd, HE n, J = 14.0 Hz, J = 7.3 Ez;; 3.3L i LE, broad, a, Z '?? tP'r., J = 14.0 Hz); 3.90 (1H, q, Me2CHCHN, J = 7.5 hZ); 4.13 (1H, m, CH 3 CH 2 OSO 2); 4.60 (2H, m, PhCH2CHN + MeCHNH); 4.65 (lH, m, PhCH2CHNH); 5.76 (1 H, d, Me 2 CHCHNH, J = 8.5 Hz); 6.216 (lH, d, Bn-CHCH = CH, J = 15.0 Hz); 6,316 (1H, d, MeCHCH = CH, J = 15.4 Hz); 6.395 (1H, d, i-? RZ = IE = _ ^ .I = L5.3 E?.; 6.477 (LE, dd, MeCHCH = CH, J = 15.4 Hz, J = 5.0 Hz); 6.748 (1H, dd, i-PrCHCH = CH, J = 15.3 Hz, J = 7.5 Hz); 6.810 (1H, dd, BnCHCH = CH, J = 15.0 Hz, J = 4.G Hz); 7.16 (2H, d, ArH, J = 7.0 Hz), 7.24 (1H, t, ArH, J = 6.0 Hz), 7.30 (2H, t, ArH, J = 7.5 Ez), 13C-NMR (d, CDI3): 14.89 (CH3), 18.19 ( 2 x CH3);
18. 73 (CH3); 28.19 ([CH3] 3); 32.48 (CH); 39.79 (CH2Ph); 49.23 vCHN); 52.11 (CHN); 59.83 (CHN); 67.09 (OCH2); 126.67 (CH =); 127.01 (Ar); 128.72 (CH =); 123.20 (Ar); 130.05 (Ar); 143.00 (CH =); 144.87 (CH =); 146.08 (CH =); 155.32 (C = 0).
The product (XXIV), which has the following formula, is always prepared according to the present invention:
BOC -NH -CHH34-Of-SO ^ W-ai-CH --_ 3i-SO ^^ ÍPr CH, CH_Ph poav)
in a 32% yield. iH-NMR (d, CDCL3): 0.95 (3H, d, CH3CH, J = 6.8 Hz);
0. 96 (3H, d, CE3CE, J = .7 Sz;, 1.24 (3H, d, C = .CH, J = 6.99 Hz), 1.40 (9H, s. (-? 3J3C; 1.55 <1H, m, Me2CH); 2.82 (1H, dd, CHCHHPh, J = 6.93 Kz, J = 13.5 Ez); 3.0 (1H, dd, CHCHHPh, J = 4.2 Hz, J = 13.5 Hz), 3.8-4.0 (2H, m, iPrCHN + MeCHN); 4.16 (2H, d, NCH2Ph, J = 6.1 HZ); 4-5-4.-7 (2H, m.BnCHN + CHNH); 4.85 (1H, d, IJH, J = 8.6 Kz; 5.4 'LH t NH.CH.-Ph, J = 6.1 Hz - 5.65 (1H, d, NH, J = 9.04 Ez'; 6.2 - .3 S =, TU, 3 X CH = CE.}.; 7.2-. 7.4 (10H, m, ArH).
EXAMPLE e Likewise, according to the preceding examples, the following products are prepared:
-CH-CH-i rOß
(XXV)
obtained in a yield of 60%. iH-NMR (500 MHz, d, CDCL3): 0.92 (6H, t, (CH 3) 2 CHCH 2, J = 6.9 Hz); 0.96 (3H, d, CH3CHC, J = 6.5 Hz); 0.97 (3H, d, CH3CHC, J = 6.8 Hz); 1.32 (2H, m, CHCH2C); 1.35 (3H, d, CH3CHN, J = 6.9 Hz); 1.39 (3H, t, CH3CH2OS02, J = 7.0 Hz); 1.43 (9H, s, [CH3] 3C); 1.65 (1E,, Me2C? CH2); 1.90 (1E, m, Me2CHC); 2.77 (1H, dd, CHHPh, J = 13.9 Hz, J = 8.4 Hz); 3.03 (1H, dd, CHHPh, J = 13.9 HZ, J = 5.3 Hz); 3.90 (1H, m, Me2CHCHN); 4.25-4.32 (5H,, CS-gCHET -r Pñ_? 2 HN -t- iBuCHN + CE3_? 2? S02,
J = 7.0 Hz); 4.39 (1E, d, iBuCHNH, J = 7.7 Hz); 4.52 (1H, d
Fh3H2CHNH, J = 5.5 Hz); 4.56 (1H,?, IPrCKNH, J = 8.2 Hz); 5.39
(1H, d, MeCHNH, J = 7.0 Hz); 5.91 (1H, d, BnCHCH = CH, J = 15.0
Hz); 6.35 (1H, d, CH = CH, J = 14.6 Hz); 6.42 (1H, d, CH = CH, J = 14.0 Hz); 6.44 '.LE, d, i rCE2E = CE, = 14.8 Hz); 6.53 (1H, dr, BnCHCH = CH, J = 15.0 Hz, J = 5.1 Ez); 6.63 (1H, dd, CECH = VH, J = 15.1 Hz, J = 6.4 Hz); 6.74 (1H, dd, iPrCHCH = C ?, J = 14.8 Hz, J = 6.8 Hz); 7.18 (2H, d, ArH); 7.30 (1H, t, ArH); 7.35 (2H, t, ArH). 13 C-NMR (DEPT, d, CDCL 3): 14.85 (CH 3); 18.20 (CH3);
18. 63 (CH3); 21.21 (CH3); 21.66 (CH3); 22.83 (CH3); 24.58
(CH;; 28.24 ([CH3] 3); 32.39 (CE); 40.37 (CH-; 43.14 (CH2);
43. 03 (CHN); 49.57 (CHN); 55.21 (CHN); 59.56 (CHN); 67.27
< OCH2); 126.62 (CH =); 127.24 (CH =); 128.31 (CH =); 128.55 (CH =); 128.81 (CH =); 129.71 (CH =); 129.77 (CH =); 130.33
(CH =); 131.90 (CH =); 132.10 (CH =); 143.48 (CH =); 144.26 (CH =); 146.36 (CH =).
BOC-KH-CH-CH-CH -BOg ñ -CH-CH-CH-8CV * -m-CH-CH-SOrNH -CH-CH-CH-SOr B Bu CHß h CH,? o8m
obtained in a yield of 30%. iH-RN (d, CDC13): 0.92 (3H, d, CH3CHCH3, J = 6.6 Hz); 0.93 '3 ?, d, CH3CHCE-, J = 6. ? z; 1.25-1.35 (5H, m, CH3CH + i? RCH2); 1.45 (9H, s, [E3] 3J; 1.64 (1H, m, Me2CHCH2); 1.83 (1H, m, Me2CH); 2.72 (1H, dd, CHCHHPh, J = 9 Hz, J = 13.9 Hz); 3.0 ( 1H, dd, CHCHHPh, J = 4.9 Hz, J = 13.9 Hz), 3.84 (1H, m, iPrCHN), 4.04 (1H, m, M CHN): 4.1-4.3 (2H, m, BnCHN + iBuC ^ N); 4.2 (2H, d, NCH2P__, J = 6.21 __z; 5.45-5.9 (5H, m, 5 X SE.;., 6.35-6.9 (SE,, 4 XC! == E), 7.2-7.4 (10H, m, ArH) 13C NMR (DEPT, d, CDCl 3): 18.014 (CH3); 18,715 (CH3); 20,944 (CH3); 21651 (CH3) 22,821 24,582 ?; ICH3 (CHCH2); 28,225 ([CH3]. 3C); 32..535 FCH [CH3] 2); fCH2Ph 40,264) 43,077 (CH2CH); 46925 (NCH2Ph); 49060 (NCH); 49559 (NCH) 55,208 (NCH); 59363 (NCH); 126,815; 127,269; 127,870 127,975, 128,684, 128,836, 12S.705, 129,901, 130,267 130,656, 142,020, (CH =), 143,490 (CH =), 143.767 (CH =) 146,483 (CH =).
EXAMPLE 9 Always in accordance with the present invention, the following synthetic schemes were reported in the preceding examples, the product (XXVIII) was prepared as indicated in the following:
? CH-CH-SOj-NH-C-VCOOCH, I
BOC (XXVII)
To a solution of (XX) (200 mg, 0.67 mmol) converted to crc sulfonyl chloride: _r ^ _rpcr _____ rte according to the procedures already described in CE2Ci2 6 0.1 ml) under nitrogen, the hydrochloride salt of methyl ester were added Gly (169.8 mg, 1.35 mmol), DBU (205.6 mg, 1.35 mmol, 201.4 μl) and DMAP (16.5 mg, 0.135 mmol) in CH2C12 (2 ml). After 30 minutes, more DBU (0.5 equivalents, 50.3 μL, 0.34 mmol) are added. After 30 minutes, 0.5 equivalents of sulfonyl chloride (100 mg, 0.33 mmol) and 0.5 equivalents of DBU (0.34 mmol, 50.3 μl) are added. After 1 hour a phosphate buffer (10 ml) is added, the aqueous phase is extracted with CH-, C12 and the
Organic extracts are collected are dried (Na2SO4) and the solvent is evaporated under vacuum. The crude mixture thus obtained is purified by means of flash chromatography (n-pentane / AcOEt = 4/6) to give (XXVII) (285 mg, 80% yield). ^ -RMN (d, CDCl3): 1.44 (9H, S, [CH ^ C); 1.75
(3H, m, NCECÜ? ECE-,.}.; 2. L5 (LE, m, NCHCH E2); 3.4 (2H, broad,
NCHCH2CH2CH2); 3.75 (3H, S, OCH3); 3.8 (3H, d, CH-.COOC? 3,
J = 4.35 Hz); 4.4 [13., broad, NCE; 4.35 (1H, t, NHCH2COOMe, J = .3 Ez.); 6.2 i LE, rr, CE = CESC2, J = L? Ez, J = l .0 Hz); 6.6 (1H, dd, CH = CELS02, J = 15.0 Ez, J = 6.5 Hz). 13 C-NMR (d, DEPT, CDCl 3): 22,701 ^ CE2, 55%); 23,536 (CH2, 45%); 28.220 ([CH3] 3); 30,369 (CH2, 45%), 31,487 (CH2M 55%); 43,733 (CH2C0); 46.168 (CH2, 55%); 46.542 (CH2, 45%); 52,478 (OCE3:; 5 € .522: C?); 227. 032 < CE =, 55%); 127,487 (EC, 45%); 145.203 vCE =, 55%;; 145.631 (CE =, 45%) To the solution of (VI) converted to the corresponding sulfonyl chloride (133 mg, 0.447 mol) in CH2C12 (4.47 ml), under nitrogen, it is deprotected and converted (XXVII) into the salt of corresponding hydrochloride were added (84.85 mg, 0.298 mmol), DBU (90.6 mg, 0.596 tons, 88.6 μl) and DMAP (7.28 mg, 0.0596 mmol) in CH2C12 (2 ml) After 1 hour, a buffer was added of phosphate (5 ml), the aqueous phase is extracted with CH2C12 and the organic extracts are collected, dried (Na-SO4) and
evaporate to give a crude mixture, which is purified by flash chromatography (n-hexane / AcOEt = 40/60) to give the product (XXVIII) in 41% yield). 1 H-NMR (d, CDCl 3): 0.96 (6H, dd, (CH 3) 2CH, J = 1.2 Hz, J = 6.7 Hz); 1.44 (9H, s, [CH3] 3C); 1.83-1.95 (4H, m, NCHCHHCH2 + (CH3) 2CH); 2.02-2.15 (1H, m NCHCHH); 3.3-3.4 (2H,, NCH H2CH2CH2); 5.76 (3H, s, OCH3); 5.57 (2H, d, NHCH2CO, J = 5.5 Hz); 4.08-4.18 (1H, m, (CH3) 2CHCH); 4.26-4.30 (1H, m, NCH); 4.75 (1H, d, BOCNH, J = 8.2 Hz); 5.44 (1E, t, NHCH2C0, 1 = 5.2 Hz); 6.27., 2E, C? = CES02, J = 15.1 Ez,; 6.46 ilE, d, CH = ^ S02 / J = 14.97); 6.66 (2H, dd, 2 x CH = CHS02, J = 5.5 Hz, J = 14.7 Hz). 13 C-NMR (d, CDCl 3): 18,176 (CH 3); 18,769 (CH3); 23,927 (CH2); 28.173 ([CH3] 3); 31,549 (CH); 31,858 (CH2); 43.S35 (CH2); 48,712 (CH2); 52.573 OC? 3; 56.655 ÍCH); 55,257 (CH); 124,555 (CH =); 128.911 (CH =); 144.349 (CH =); 145,616 (CH =). In addition, the following products were prepared:
BOC-I-H -CH-CH-CH -8Q -NH -CH- Oi-Ol -SO * -fßl írCOOCH, ^ CHiDH flOOQ
^ -RMN (d, CDCL3): 0. 97 (3E, d, C? 3CH, J = 6 .7 Ez); 0 97 (3H, d, CH 3 CH, J = 6. 9 Hz); 1.46 (9H, s, [CH3] 3C); 1 . 85
(1H, m, Me2CH); 3.52 (1H, dd, CHHOH, J = 6.7 Hz, J = 11.7 Hz); 3.78 (3H, s, OCH3); 3.84 (1H, dd, CHHON, J = 3.8 Hz, J = 11.7 Hz); 3.91 (2H, d, CH2COO, J = 5.87 Hz); 3.9-4.1 (2H, m, 2 x CHN); 4.88 (1H, d, NH, J = 7.5 Hz); 5.42 (1H, d, NH, J = 6.9 Hz); 5.78 (1H, t, NHCH2, J = 5.8 Hz); 6.39 (1H, d, CH = CHS02, J = 15 Hz); 6.57 < 1H, dd, CH = CHS02, J = € .6 Hz, J = 15 Hz); 6.65 (2H, s,
CH = CHSO2; . 13C-EMN (d, D? FT, C | 3;: 16.367 ^ CE3; 18.653 (CH3); 28.220 ([CH3] 3); 31.446 'M 2__E - 43.937 (CHjCOO); 52.681 - = 3; 55.563 CH5", -? ~. L ~ Z = .63.4LE ^ CH2C; 129.494 (CE =); 131.063 (CH =); 143.5L3 3? =; 143.542 (CH =).
BOC-HH - jH-CH-CH -SO »- NH-CHrCOOCH * CHzCH2CONHCPhj (XXX)
iH-NMR (d, CDCL3): 1.45 (9H, s, [CH3] 3); 1.5-2.0 (2H, m, CH2CH2CO); 2.45 (2H, t, CH2CH2CO, J = 7.8 Hz); 3.75 (3H, s, OCH,); 3.9 (2H, t, NEC ^ COO, J = 3.48 Ez); 4.4 (1H, broad, NHCH); 5.2 (1H, broad, BOCNE.), - 6.3 (1H, d, CH = CHSO, J = 15.2 Hz), 6.65 (1H, dd, CH = CHS02, J = 15.2 Hz, J = 5.2 Hz); 6.85 (1H, s, N? CP-13); 7.15-7.4 (15H, m, ArH).
EXAMPLE 10
In addition, the following methanesulfonyl derivatives were prepared by reaction of the corresponding amine hydrochlorides with methanesulfonyl chloride:
CHaSO_NH -CH-CH-CH-80t-NHCHrf > 0 °° ®
obtained in a 70% yield. iH-NMR (d, CDCL3): 1.34 (3H, d, CH3CH, J = 7.1 Hz);
2. 96 (3E, s .C? 3SO-. ';; 4.23 (3H, d, NC ^ Pr + NHCE, J = 6.1 Ez);
4. 74 (1H d, MeSC2N, J = 8.3 Ez); 5.CL i LE, t, S02NHBn, J = 6. L
Hz); 6.38 (LE, dd CE = CHSC2, J = l.6 Hz, J = 15.1 Hz); 6.66 (1E, dd, CH = CS02, J = 5 Hz, J = 15.1 Hz); 7.35 (5H, m, ArH).
CtfcSCVft. -CH-O CU -SQt-WH -CH -CH-CH -ßOjHCHßP-
obtained in a yield of 83%. iH-RN (d, CDCL3): 0.897 (3H, d, CH3, J = 3.2 Hz); 0.98 (3E, d, C? 3, J = 3.2 Hz); 1.35 (3E, d, CH3, J = 6.5 Hz); 1.85 t__E. m. -2 CE.- 5. 2-3S .3Hf S. -S-SC-. '; 3.85 (1E, __, CHCH (CH3) 2); 4.15 (3H, m, CHCH3 + CH2); 5.5 (3H, m, 3 X NH); 6.4 (1H, &, CH (i_Pr) CH = (_ HS02, J = 15 Hz.};; 6.45 (1H, d, CH (CH,) C & = CHSC-, J = 14-2 Ez); '1H, d, CH (iPr) CH = CHSO-, J = 15 Hz); €. € 5 (1H, dd, CH (CH3) CHS02, J = 4.48 Hz, J = 14.2 Hz).
Claims (28)
1. Derivatives of aminosulfonic acids, characterized in that they have the following general formula: Y- ~ H-- < 3-H_H -__ X_H - Ss2X M i * (I) where: R is selected from: hydrogen, fragments corresponding to the side chains of natural amino acids, linear, branched or substituted or unsubstituted cyclic alkyl chains, arylalkyl chains, aryl and heteroaratpathic groups; Y indicates hydrogen, including the possible salt forms of the corresponding amine, or any protective group commonly used for the protection of the amine groups; X denotes Cl, OH, OCH2CH3, OCH3, ONBu4, NHCH2Ph, with the proviso that: when Y is chosen from PhCH2CO, CH3) 3COCO and X is chosen from OCH2CH3, 0NBu4 or when Y is chosen as PhOCH2CO and X is chosen as OCH2CH3 or when Y is a salt form of the corresponding amine and X is chosen as OH, R is different from CH3.
2. The aminosulfonic acid derivative according to claim 1, characterized in that R is chosen equal to -CH3, Y is chosen equal to the protecting group (CH3) 3C-OCO- and X is chosen equal to Cl.
3. The aminoeiphonic acid derivative according to claim 1, characterized in that Y is chosen equal to hydrogen and the corresponding amine has the form of the hydrochloride salt, R is chosen equal to CH3 and X is chosen equal to OCH2CH34. The amino acid derivatives according to claim 1, characterized in that R is chosen from the side chains of the proteinogenic amino acids, and is equal to Q - ^, where R-, is chosen from -CH3 and -CH2CH3, according to the following formula:
(H) with the proviso that: when R ^ is -CH2CE. , R is different from CH-,.
5. The derivative gives aminosulfonic acids of cc__fcrity with claim 4, characterized perqu R is equal to (C ^ J-jCH- and R. ^ is equal to -CH2CH3.
. The aminosulf acid derivative of cenfer-i a with reivipdicacicr 4, characterized in that E __ = i ra a ~~ *? 5"* • * ^^ water__ a - > .n- ^.
7. The derivatives of aminosulfonic acids, .s because they have the following general formula: where: R is selected from: hydrogen, fragments corresponding to the side chains of natural amino acids, linear, branched or substituted or unsubstituted cyclic alkyl chains, arylalkyl chains, aryl and heteroaromatic groups; Y indicates hydrogen, including the possible salt forms of the corresponding amine, or any protecting group commonly used for the protection of the amine groups; X indicates Ci, OH, OCS2? -5, OC? 3, ONBu *, KHCE- ???, which are functionalized double bonds, with the insertion in the alpha-beta position of a cyclopropane group.
8. The derivatives of aminosulphonic acids, cararenced because they have the following formula g______ral: Y-N CH-CH-rCH-SOjX where: R is the i ge between: hydrogen, corresponding to the side chains of natural ainipf-SHrfnc, linear, branched or cyclic alkyl chains substituted or unsubstituted, arylalkyl chains, aryl and heteroaromatic groups; Y indicates hydrogen, including the possible salt forms of the corresponding amine, or any protecting group commonly used for the protection of the amine groups, - X indicates Ci, CE, = 2'Z = -, OCE3, ON3u4, NEZ? 2Fh, When the Y is chosen between? hCH2CO, (CH.}. ^ C0C3; and X sa e __ "_ xrt-_c as _J ___ j-_ or when Y is a corresponding salt of the amine and X is chosen as OH, R is different from CH3, which are functionalized double bonds with the insertion, in the alpha-beta position, of an epcxt group.
9. The use of aminosulfonic acid derivatives having the following general formula: Y- H CH-CH-TCH-SO_X H I where : R is selected from: hydrogen, fragments corresponding to the side chains of natural amino acids, linear, branched or substituted or unsubstituted cyclic alkyl chains, arylalkyl chains, aryl and heteroaromatic groups; Y indicates hydrogen, including the possible salt forms of the corresponding amine, or any protective group commonly used for the protection of the amine groups, - X indicates Cl, CE, OCE2CE3, OC_? 3, 0S3u4, NHCE2P, as syntheses in the synthesis of pseudopeptides.
10. Pseudopeptides obtained through the use of the syntheses according to claim 5, characterized in that they have at least one sulfonamide type bond conjugated to a double bond.
11. The pseudopeptides according to claim 10, characterized in that they have the following formula: where R ~ is selected from hydrogen, fragments corresponding to the side chains of natural amino acids, linear, branched or substituted cyclic alkyl chains c = ir. substitute, arrlalgullo chains and aryl and heteroaracáticos groups, and is either equal to c different from R.
12. The pseudopeptide of comfort with the claim LL characterized in that Y e = equal to the protective group (CE- 'Z-OCC-, R is' equal -_? - = _ £ _ v X equals NHCH-, Ph.
13. pseudopeptide of confo__Epity cs. r- < ai vi ndí parj? n "i" < characterized by that Y e = equal to the aruz-O protector (CH3) -, C-OCO-, R is equal to R2 and is equal to CH3 and X is equal to -OCH2CH3.
14. The pseudopeptide of pnnfnmri fbr ^ GTG? Claim 11, characterized in that Y is equal to the group protective (CH3) 3C-OCO-, R is CH3, R2 and is (CH3) 2CH- and X is equal to OCH2CH3.
15. The pseudopeptides according to claim 10, characterized in that they are functionalized to at least one double bond in the alpha-beta position compared to the sulfsamide group, giving an epoxy or cyclopropane group.
2 . ___. process for the preparation of sulphonic amino acid derivatives according to claim 1, characterized in that it comprises the following steps: - conversion of a natural alpha-amino acid to an alpha-aminoaldehyde, - conversion of c-lfa-to-prnoaldehyde in the derivate of aminosulfonic acid by means of the Witting-Horner reaction.
17. The process for the preparation of aminosulphonic acid derivatives in accordance with the claim 16, characterized in that the natural alpha-amino acids are proteinogenic amino acids either in the form of (L) or in the form of ("Di.
18. The process for the preparation of pseudopeptides according to claim 10, characterized in that it comprises the following steps: - transformation of a gamma-amino-alpha, beta-unsaturated sulfonic ester derivative of (I) into a corresponding sulfonate salt, - activation of the suifonate sai, with production of an activated sulfonate sai, coupling of the activated sulfonatc salt and the deposition of ammonium acids (I), suitably activated to the amine group, with the production of a pseudopeptide having a sulfonamide bond.
15. The process for the preparation of sepspeptides, characterized in that the pseudopeptide according to claim 11, is subjected to release and activation, alternatively of the amine or sulphonic group, and to additional storage with (I) suitably activated, performing this Thus, a process of the iterative type, with the production of a pseudopeptide provided with sulfonamide bonds.
20. The process for the preparation of pseudopeptides according to claim 10, characterized in that it comprises the following steps: - transformation of a gamma-amino-alpha, beta-unsaturated sulfonic ester derivative of (I) into a corresponding sulfonate salt, - activation of the sulfonate salt, with production of an activated sulfonate salt, coupling of the activated sulfonatc salt and an appropriately activated native aminc-accr-c, with the production of a pseudopeptide provided with a sulfonamide bond, and provided with at least one free carboxyl group, protected, salified or activated.
21. The process for the preparation of pseudopeptides, characterized in that the pseudopeptide according to claim 20 is subjected to release and activation of the amine group or the carboxylic group alternatively and to an additional coupling with a natural amino acid or with (I) suitably activated, performing This is a process of the iterative type with the production of a pseudopeptide provided with at least one sulfonamide bond.
22. Derivatives of aminosulfonic acids that have the following chemical formulas: BOC-NH ^ H- H-CH-SOj-OCHjCHi J 003.}. CH ^ CH ^ ONHCPhs
2. 3 . Derivatives of aminosulphonic acids that have the following chemical formulas: CHaSCjI-H H_H-Qi ^ B -SOt? MCH¿sh I CHjSQzNH
24. Pseudopeptides provided with at least one sulfonamide-type bond conjugated to a double bond in accordance with claim 10, characterized in that they have the following chemical formulas: BOC -NH -CH-CH- H-SO ^ NHHW ^ H-Oi-Ssa-NH-OT-CH-CH-SOrOT CHaPta CH, lPr (XX1IQ BOC -NH - -t-CH-O-SO ^ -CH-CH-OI-βC .- ^ Pr CH, sv * (X50V)
25. Pseudopeptides provided with at least one linkage of the suifonamide type conjugated to a linkage according to claim 13, characteristically having the following chemical formulas: BOC-fM ^ CH- CX.CH-50_ «-CH-CH-CH-60.NH-H-CH-CH-SOrWH -CH-CH-CH-ßOrOH I 'c • Bu CHi h CHt ** ßOC? W SOx H -CH-CH-CH-SOrOa
26. Pseudopeptides provided with at least one sulfonamide-type conjugated link to a double bond obtainable in accordance with claim 20, are rarefied because they have the chemical formulas: 80C-NH-CH-CH-CH-SO, - NH-CHrCOOCH, CHjCHjCOKHCP !} , (XXX) BOC-NH - < H-CH-CH-SO_ -NH -CH- CH-CH-SO, -NH-C-VCOOCH, Pr ¿^ (xxa)
27. Derivadrs of acides aminreuif onyxes that have the following cryomic formula: X »| í /? _a-CH -SOj-OCHß poq
28. Pseudopeptides provided with at least one trp link to conjugates to a double bond ?? CH-CH -S £ 3 »-NrW-Hi OOCH, SO_ -CH-CH -CH -NH-ßOC p_ POWH)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI940989A IT1269511B (en) | 1994-05-17 | 1994-05-17 | AMINO-SULPHONIC ACID DERIVATIVES, THEIR USE IN THE SYNTHESIS OF PSEUDOPEPTIDES AND PROCEDURE FOR THEIR PREPARATION |
MIMI94A000989 | 1994-05-17 | ||
PCT/EP1995/001788 WO1995031433A1 (en) | 1994-05-17 | 1995-05-11 | Derivatives of aminosulfonic acids, utilization of the same in the synthesis of pseudopeptides and process for their preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9605426A MX9605426A (en) | 1998-05-31 |
MXPA96005426A true MXPA96005426A (en) | 1998-10-23 |
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