2-Hydroxy-Mutilin Carbamate Derivatives for Antibacterial Use

专利摘要:
The present invention relates to 2- (S) -hydroxymutillin carbamate derivatives of formula (I) which are useful for treating bacterial infections. <Formula I> In the formula, R 1 is a 5- or 6-membered optionally substituted heteroaryl group; R 2 is vinyl or ethyl.
公开号:KR20030011815A
申请号:KR1020027013202
申请日:2001-03-29
公开日:2003-02-11
发明作者:제랄드 브룩스；에릭 헌트；스티븐 하워드
申请人:스미스클라인비이참피이엘시이；
IPC主号:

专利说明:

2-Hydroxy-Mutilin Carbamate Derivatives for Antibacterial Use}
[2] Pleuromutillin, a compound of Formula A, is a natural antibiotic having antimycoplasma activity and moderate antibacterial activity. Mutiline and other compounds with free OH at C-14 are inert. The effect of other modifications on C-14 on the activity of pleuromutillin has been studied [H. Egger and H. Reinshagen, J. Antibiotics, 1976, 29, 923]. Substitution of the hydroxy group of the glycolic acid ester residue at position 14 with other O, S or N-linking groups has been found to enhance antimicrobial activity. Thus, the introduction of a diethylaminoethylthio group is a compound of formula (B), which is also known as thiamuline used as a veterinary antibiotic [G. Hogenauer in Antibiotics, Vol. V, part 1, ed. F.E. Hahn, Springer-Verlag, 1979, p. 344].
[3]
[4]
[5] In this use, G. Hogenauer, loc. The unusual naming scheme commonly used in cit.] is used.
[6] In particular, acyl carbamate 14-O- of the non-motilin together _{^{(R a CONR b CO 2 -}} ) derivatives (where, R ^a may have a range of values, including optionally substituted heterocyclic group, R 1 ^b is various WO 97/25309 (SmithKline Beecham), which is selected from an optional group), describes the modification of acyloxy groups.
[7] In addition, WO 98/05659 (SmithKline Beecham) describes 14-O-carbamoyl derivatives of mutiline acylated with groups wherein the N-atom of the carbamoyl group contains azabicyclic moieties.
[8] In addition, WO 99/21855 (SmithKline Beecham) describes derivatives of mutilin or 19,20-dihydromutiline with modified glycolic acid ester residues at the 14 position. In such compounds, the 2 position (α position with respect to the keto group) may be substituted with hydroxy. However, most of the compounds illustrated herein do not have such substituents.
[9] 19,20-dihydro-2α-hydroxy-mutiline is also described in G. Schulz and H. Berner in Tetrahedron, 1984, vol. 40, pp 905-917.
[1] The present invention relates to novel compounds, methods of making them, pharmaceutical compositions comprising them and their use in medical treatments, in particular antibacterial treatments.
[10] The present invention is based on the unexpected finding that certain novel 14-O-carbamoyl derivative mutilin derivatives further having a (2S) -hydroxy substituent have strong antimicrobial activity.
[11] Accordingly, the present invention provides a compound of formula (I)
[12]
[13] In the formula,
[14] R ¹ is a 5- or 6-membered optionally substituted heteroaryl group;
[15] R ² is vinyl or ethyl.
[16] In this series of compounds, it has been found that introducing (2S) -hydroxy substituents imparts greater metabolic stability to liver enzymes as compared to the corresponding 2-unsubstituted counterparts.
[17] Examples of heteroaryl groups in R ¹ include 5 or 6 membered single rings containing 1 or 2 nitrogen atoms and optionally containing other heteroatoms selected from oxygen or sulfur, for example pyridine, pyridazine, pyri Midines, pyrazine, isoxazoles, thiazoles, imidazoles, pyrazoles; Or five or six membered rings containing three nitrogen atoms, for example 1,2,3-triazole, 1,2,4-triazole; Or groups having a 5 or 6 membered ring, for example benzimidazole, containing 1 or 2 nitrogen atoms fused to a benzene ring. Another example of a heteroaryl group at R ¹ is a 5 membered group containing 1 or 2 nitrogen atoms fused to another 5 or 6 membered optionally substituted heteroaryl ring containing 1 or 2 nitrogen atoms or Groups having 6 membered rings are included.
[18] Representative examples of such heteroaryl groups for R ¹ include pyridine, pyrazine, pyridazine, 3-oxo-3,4-dihydropyrido [2,3-b] pyrazine, pyrazolo [1,5-a] pyridine Midines, pyrimidines and thiazoles. Examples of such heteroaryl groups for R ¹ are pyridine, pyrimidine and thiazole.
[19] Representative optional substituents on R ¹ include amino, mono- or di- (C _1-6 ) alkylamino, (C _1-6 ) alkyl, (C _1-6 ) alkoxy, nitro and N-containing heterocyclyl, eg For example piperidin-4-yl which may be optionally substituted. Typically R ¹ may contain 1 or 2 substituents.
[20] The term "aryl" as used herein, unless otherwise defined, means phenyl or naphthyl. Substituted aryl groups contain up to 5, preferably up to 3 substituents.
[21] Suitable substituents for aryl groups, including phenyl when forming part of a benzoyl group, include, unless otherwise defined, halogen, (C _1-6 ) alkyl, aryl, aryl (C _1-6 ) alkyl, (C _{1 -6} ) alkoxy, (C _1-6 ) alkoxy (C _1-6 ) alkyl, halo (C _1-6 ) alkyl, aryl (C _1-6 ) alkoxy, hydroxy, nitro, cyano, azido, amino , Mono- and di-N- (Ci_ ₆ ) alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxylate, carboxy ester, carbamoyl, mono- and di-N- (C _{1 -6} ) alkylcarbamoyl, (C _1-6 ) alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C _1-6 ) alkylguanidino, amidino, (C _1-6 ) Alkylamidino, sulfonylamino, aminosulfonyl, (C _1-6 ) alkylthio, (C _1-6 ) alkylsulfinyl, (C _1-6 ) alkylsulfonyl, heterocyclyl, heteroaryl, heterocycl Aryl (C _1-6 ) alkyl and heteroaryl (C _1-6 ) alkyl. In addition, the carbon atoms of two adjacent rings may be joined by a (C _3-5 ) alkylene chain to form a carbocyclic ring.
[22] As used herein, the terms "alkyl" and "alkenyl" refer to straight and branched chain groups containing up to 6 carbon atoms (either individually or as part of alkoxy or alkenyloxy).
[23] As used herein, the terms "cycloalkyl" and "cycloalkenyl" refer to groups having from 3 to 8 ring carbon atoms.
[24] When an alkyl, alkenyl, cycloalkyl or cycloalkenyl group is substituted they may comprise up to 4 substituents, preferably up to 2 substituents. Suitable substituents for alkyl, alkenyl, cycloalkyl or cycloalkenyl groups include aryl, heteroaryl, heterocyclyl, (C _1-6 ) alkoxy, (C _1-6 ) alkylthio, aryl (C _1-6 ) alkoxy, Aryl (C _1-6 ) alkylthio, amino, mono- or di- (C _1-6 ) alkylamino, cycloalkyl, cycloalkenyl, their carboxy and esters, amides, ureido, guanidino, (C _1-6 ) alkylguanidino, amidino, (C _1-6 ) alkylamidino, (C _1-6 ) acyloxy, azido, hydroxy and halogen.
[25] As used herein, the terms "heterocyclyl" and "heterocyclic" refer to single and fused non-aromatic, suitably containing up to four heteroatoms selected from oxygen, nitrogen, and sulfur in each ring unless otherwise defined. Means a ring. Each heterocyclic ring preferably has 4 to 7, preferably 5 or 6 ring atoms. The fused heterocyclic ring system may comprise a carbocyclic ring and only needs to include one heterocyclic ring.
[26] When a heterocyclyl group is substituted, it may contain up to three substituents. Substituents for the heterocyclyl group are preferably selected from oxo and the groups defined above with suitable aryl substituents.
[27] The term "heteroaryl" as used herein, unless otherwise defined, includes mono- or bicyclic heteroaromatic ring systems containing up to four, preferably one or two, heteroatoms each selected from oxygen, nitrogen, and sulfur. do. Each ring may have from 4 to 7, preferably 5 or 6 ring atoms. Bicyclic heteroaromatic ring systems can include carbocyclic rings.
[28] When a heteroaryl group is substituted, it may contain up to three substituents. The substituent of the heteroaryl group is preferably selected from the groups defined above as suitable aryl substituents.
[29] Depending on the substituent, two or more diastereomers may be possible. In this case, the present invention includes each diastereomer and mixtures thereof.
[30] 2-hydroxy-substituted compounds of formula (I) are in the 2- (S) configuration.
[31] Preferred compounds of the present invention include the following compounds:
[32] 6-amino-3-pyridinylcarbonylcarbamic acid 2- (S) -hydroxymutinine 14-ester;
[33] 2-amino-5-pyrimidinylcarbonylcarbamic acid 2- (S) -hydroxymutinine 14-ester;
[34] 2-Amino-5-thiazolylcarbonylcarbamic acid 2- (S) -hydroxymutyline 14-ester; And
[35] 2-Amino-4-thiazolylcarbonylcarbamic acid 2- (S) -hydroxymutyline 14-ester.
[36] More preferred compounds include the following compounds:
[37] 3-Amino-6-pyridazinylcarbonylcarbamic acid 2- (S) -hydroxymutillin 14-ester;
[38] (2,6-diamino-4-pyrimidinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
[39] (5-Amino-6-methoxy-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
[40] (5-Amino-6-methoxy-3-pyridinylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester;
[41] (6-amino-3-pyridinylcarbonyl) carbamic acid 19,20-dihydro 2- (S) -hydroxymutinine 14-ester;
[42] [2- (1-piperazinyl) -5-pyrimidinylcarbonyl] carbamic acid 2- (S) -hydroxymutinine 14-ester;
[43] (2-methylamino-5-pyrimidinylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester;
[44] (6-amino-5-methoxy-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester;
[45] (6-dimethylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester; And
[46] (6-Methylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester.
[47] Particularly preferred compounds include the following compounds:
[48] (5-Amino-6-methoxy-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
[49] (5-Amino-6-methoxy-3-pyridinylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester;
[50] (6-Amino-3-pyridinylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester;
[51] (6-dimethylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester; And
[52] (3-Amino-6-pyridazinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester.
[53] The compounds of the present invention may be crystalline or amorphous and, in the case of crystalline forms, may be optionally hydrated or solvated. The present invention includes within its scope not only stoichiometric hydrates but also compounds containing varying amounts of water.
[54] The compounds according to the invention are in substantially pure form, for example at least 50% pure, suitably at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure. It is suitable, in particular, to be provided with a purity of at least 98%, where all percentages are calculated by weight / weight.
[55] Compounds of the invention containing basic groups such as amino substituents may be in the form of free base or acid addition salts. Compounds having acidic groups, such as carboxy substituents, may be in the form of pharmaceutically acceptable salts. Compounds of the invention having both basic and acidic centers may be in the form of zwitterions, acid addition salts of basic centers or alkali metal salts (of carboxyl groups). Pharmaceutically acceptable salts are preferred.
[56] Pharmaceutically acceptable acid addition salts are described in Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19]. Suitable salts include hydrochloride, maleate and methanesulfonate, with hydrochloride being particularly preferred.
[57] Pharmaceutically acceptable salts include the salts described in Berge, Bighley and Monkhouse, J. Pharm, Sci., 1977, 66, 1-19. Suitable salts include alkali metal salts such as sodium and potassium salts.
[58] In another aspect, the invention provides compounds of formula II wherein R ^1A CONCO, wherein R ^1A is R ¹ as defined above or a group convertible to R ¹ , such as a group comprising a protected substituent React with acyl isocyanate of
[59] (a) deprotecting the X and / or P groups to produce hydroxyl groups at the 11 and 2 positions, respectively,
[60] (b) converting the R ^1A group to R ¹ , eg removing a protecting group,
[61] (c) converting the R ¹ group to another R ¹ group, and
[62] (d) hydrogenating the vinyl group at position 12 to form an ethyl group
[63] It provides a method for producing a compound of formula (I) comprising a.
[64]
[65] Wherein X and P are hydrogen or a hydroxyl protecting group such as an acyl group, and R ² is as defined above.
[66] Preference is given to using compounds of the formula (II) in which both P and X are hydroxyl protecting groups.
[67] Similar methods have already been disclosed in WO 97/25309 and WO 98/05659 (SmithKline Beecham).
[68] Methods for preparing acyl isocyanates are described in the literature. For example, it can be used as an acid chloride (R ^1A COCl) in silver inert solvents such as benzene, toluene, chloroform, dichloromethane or 1,2-dichloroethane (see, eg, Murdock and Angier in J. Org). Chem., 1962, 27, 3317), tri-n-bunyl tin isocyanate (as described, for example, in Akteries and Jochims, Chem. Ber., 1986, 119, 83). Or trimethylsilyl isocyanate (as described, eg, in Sheludyakov et al., J. Gen. Chem. USSR, 1977, 2061-2067). Alternatively, it may be prepared by treating a primary amide (R ^1A CONH ₂ ) or an N, N-bis (trimethylsilyl) derivative thereof with oxalyl chloride or phosgene in an inert solvent (eg, Spziale and Smith, J. Org.Chem., 1962, 27, 3742; Kozyukov et al., Zh Obshch Khim, 1983, 53, 2155].
[69] The preparation and reaction of acyl isocyanates can be conveniently carried out in one step. It is usually silver cyanate and tertiary base (eg triethylamine, diisopropyl ethylamine, pyridine) in an inert solvent (eg chloroform, dichloromethane, 1,2-dichloroethane), generally Reaction of the compound of formula II with the acid chloride R ^1A COCl in the presence of triethylamine.
[70] Thus, in another aspect the invention reacts a compound of formula II with an acyl chloride compound of formula R ^1A COCl in the presence of a base such as silver cyanate, and triethylamine, and, if necessary, in the following preferred order: Provided is a process for preparing a compound of formula (I) comprising performing one or more of the steps:
[71] (e) deprotecting the P and / or X groups to produce hydroxyl groups at the 2 and 11 positions, respectively,
[72] (f) converting the R ^1A group to R ¹ , eg removing a protecting group,
[73] (g) converting the R ¹ group to another R ¹ group, and
[74] (h) hydrogenating the vinyl group at position 12 to form an ethyl group.
[75] Preference is given to using compounds of the formula (II) in which both P and X are hydroxyl protecting groups.
[76] Suitable hydroxyl protecting groups are well known in the art and can be removed without disrupting the molecules remaining under conventional conditions. A comprehensive discussion of how hydroxy groups can be protected and how to isolate the resulting protective derivatives are described, for example, in "Protective Groups in Organic Chemistry" (TW Greene and PGM Wuts, Wiley-Interscience, New York, 2nd edition, 1991). Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as trialkylsilyl and also organocarbonyl and organooxycarbonyl groups such as acetyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4- Nitrobenzyloxycarbonyl is included.
[77] Representative values for P include acetate, dichloroacetate or trifluoroacetate, with dichloroacetate being preferred. Representative values for X include acetate, dichloroacetate or trifluoroacetate, with trifluoroacetate being preferred. After the 14-O-carbamoyl derivative is formed, the 2- and 11-acyl groups can be removed by selective hydrolysis (eg using NaOH in MeOH).
[78] ^Protective groups such as amino, carboxy, hydroxy which can be used as substituents in R ^1A are well known in the literature. See, eg, "Protective Groups in Organic Chemistry" (TW Greene and PGM Wuts, Wiley-Interscience, New York, 2nd edition, 1991). Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as trialkylsilyl and also organocarbonyl and organooxycarbonyl groups such as acetyl, aryloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4- Nitrobenzyloxycarbonyl is included. Particularly suitable carboxy protecting groups include alkyl and aryl groups such as methyl, ethyl and phenyl. Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
[79] Compounds of formula (I), wherein R ¹ = Et, have a palladium catalyst (eg, 10% palladium on carbon) in a solvent such as ethyl acetate, ethanol, dioxane or tetrahydrofuran before or after carbamoylation of the compound of formula II. It can manufacture by reducing vinyl group R <^1> by hydrogenation using
[80] Compounds of formula (II), wherein both P and X are hydroxyl protecting groups, are novel intermediates used to prepare compounds of formula (I).
[81] Thus, in another aspect, the present invention relates to compounds of the invention wherein P and X are hydroxyl protecting groups, in particular organocarbonyl groups, for example (C _1-6 ) alkylcarbonyl groups, such as trifluoro, wherein alkyl moieties may be substituted with 1 to 3 halogen atoms. There is provided a compound of formula II which is roacetyl and dichloroacetyl. It is preferred that P is dichloroacetyl and X is trifluoroacetyl. Preferred compound of formula (II) is (2S) -2-dichloroacetoxy-11-O-trifluoroacetyl-mutiline.
[82] Compounds of formula (II) can be prepared from mutilin via an intermediate 2-diazo compound, analogous to the method described in HBerner et al., In Monatshefte fur Chemie, 1981, vol. 112, pp 1441-1450. Do. This intermediate can then react with the carboxylic acid to form a 2-acyloxy-mutinine derivative. Typically, 2-dichloroacetoxy-mutiline derivatives are prepared by reaction with dichloroacetic acid.
[83] Preferred synthetic routes of the compounds of formula (I) are shown in the following schemes.
[84]
[85] The following reagents and conditions were used:
[86] (i) ethyl formate, sodium methoxide, toluene, room temperature;
[87] (ii) KOH / EtOH, room temperature;
[88] (iii) tosyl azide, triethylamine, dichloromethane, -10 ° C to room temperature;
[89] (iv) dichloroacetic acid, dichloromethane, 0 ° C. to room temperature;
[90] (v) trifluoroacetyl imidazole, tetrahydrofuran, room temperature;
[91] (vi) R ^1A COCl, silver cyanate, triethylamine, dichloromethane, room temperature;
[92] (vii) 0.5 M KOH, EtOH, room temperature.
[93] Since the compounds of the present invention can have chiral centers, a mixture of diastereomers can be prepared in this manner. Single diastereomers can be prepared by isolating mixtures of such diastereomers by conventional techniques such as chromatography or fractional crystallization.
[94] The compounds of the present invention may be crystalline or amorphous and, in the case of crystalline forms, may be optionally hydrated or solvated. If some of the compounds of the present invention are crystallized or recrystallized from organic solvents, the crystallization solvent may be present in the crystalline product. Likewise, some of the compounds of the present invention may be crystallized or recrystallized from solvents containing water. In such cases, hydrated water may be present in the crystalline product. Crystallization methods usually produce stoichiometric hydrates. Compounds containing varying amounts of water can be prepared by methods such as freeze drying.
[95] The compounds according to the invention are in substantially pure form, for example at least 50% pure, suitably at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure. It is suitable, in particular, to be provided with a purity of at least 98%, where all percentages are calculated by weight / weight. Impure or less pure forms of the compounds according to the invention can be used, for example, to prepare more pure forms of the same compound or related compounds (eg corresponding derivatives) suitable for pharmaceutical use.
[96] In addition, the present invention includes pharmaceutically acceptable salts and derivatives of the compounds of the present invention. Salt formation may be possible when one of the substituents has an acidic or basic group. Salts can be prepared by salt exchange in a conventional manner.
[97] Acid addition salts may or may not be pharmaceutically acceptable. In the latter case, such salts may be useful for the isolation and purification of the compounds of the present invention or intermediates thereof, which are subsequently converted to pharmaceutically acceptable salts or free bases.
[98] The compounds of the present invention and pharmaceutically acceptable salts or derivatives have antibacterial properties and are therefore used for the treatment of microbial infections, in particular in animals, in particular in mammals, including humans, in particular in humans and livestock (including farm animals). Compounds are, for example, Staphylococcus aureus , Staphylococcus epidermidis , Enterococcus faecalis , Streptococcus pyogenes , Streptococcus agalactiae , Streptococcus pneumoniae , Haemophilus sp. , Neisseria sp. , Legionella sp. , Chlamydia spp. Gram-positive and Gram-negative bacteria and Mycoplasma , including Chlamydia sp. , Moraxella catarrhalis , Mycoplasma pneumoniae and Mycoplasma gallisepticum It can be used to treat infection by.
[99] In addition, the present invention comprises administering a compound of the present invention or a pharmaceutically acceptable salt or derivative or solvate thereof, or a composition according to the present invention to a patient in need thereof. Provides a way to treat it.
[100] The compounds of the present invention show good activity against Chlamydia pneumoniae . It has been associated with heart disease, in particular vascular infection (see, eg, FR 2 771 008-A1, Hoechst Marion Roussel SA). Thus, in another aspect, the present invention provides a method for preventing atherosclerosis induced in chlamydia pneumoniae, comprising treating a subject in need thereof with an effective amount of a compound of formula (I). In addition, the compounds of formula (I) can be used in combination with anti-atherogenic agents to reduce the incidence of heart attacks and other heart diseases. Representative examples of anti-atherosclerotic agents include a group of cholesterol lowering compounds, commonly referred to as "statins" such as atorvastatin (Lipitor, Warner Lambert), pravastatin (Livavas, Merck), and cerivastatin (Baycol). Bayer). It has also been suggested that Chlamydia pneumoniae can contribute to Alzheimer's disease. Thus, in another aspect, the present invention provides a method of treating Alzheimer's disease comprising treating a subject in need thereof with an effective amount of a compound of formula (I).
[101] The present invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament for use in the treatment of a microbial infection.
[102] The compounds of the present invention can be used to treat skin and soft tissue infections and acne by topical administration. Thus, in another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament for topical administration for the treatment of skin and soft tissue infections and also for the treatment of acne in humans. To provide.
[103] In addition, the compounds of the present invention are administered intranasally by pathogenic bacteria such as Staphylococcus aureus, H. influenzae , Streptococcus pneumoniae and Moraxella catarrhalis by administering a compound of the invention. In particular, it can be used to eliminate or reduce metastasis of nasopharynx by these bacteria. Thus, in another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament suitable for intranasal administration for reducing or eliminating intranasal migration of pathogens. to provide. It is preferable to use the medicament for intensive delivery to the nasopharynx, especially the nasopharynx.
[104] This reduction or elimination of intranasal migration can prevent the occurrence of recurrent acute bacterial sinusitis (RABS) or recurrent otitis media in humans, in particular to reduce the number of episodes occurring in a patient over a period of time or to increase the interval between episodes. I find it useful. Thus, in another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament suitable for intranasal administration for the prevention of recurrent acute bacterial sinusitis or recurrent otitis media. to provide.
[105] The compounds according to the invention can be suitably administered to a patient at a dosage of 1.0 to 50 mg per kg body weight per day. In the case of adults (about 70 kg body weight) the compounds according to the invention can be administered at 50 to 3000 mg per day, for example about 1500 mg. Adult dosages of 5 to 20 mg / kg are suitable daily. However, it may be used in higher or lower dosages according to general clinical practice.
[106] In order to reduce the risk of developing resistant bacteria during the prevention of recurrent otitis media or recurrent acute bacterial sinusitis, the drug is preferably administered intermittently rather than continuously. In intermittent treatment suitable for the prevention of recurrent otitis media or recurrent sinusitis, the drug is administered daily for a short period of time, for example 2 to 10 days, suitably 3 to 8 days, more suitably about 5 days, After the interval, the administration is repeated every month, for example over several months, for example for up to six months. Less preferably, the drug may be administered continuously for an extended period of time, for example for several months. Suitably, the drug is administered once or twice a day for the prevention of recurrent otitis media or recurrent sinusitis. Suitably, the drug is administered during the winter season when bacterial infections such as recurrent otitis media and recurrent sinusitis are more prevalent. The drug may be administered 0.05 to 1.00 mg, typically about 0.1 to 0.2 mg, once or twice daily to each nostril.
[107] More generally, the compounds and compositions according to the invention may be formulated with other antibiotics for administration in any conventional manner for use in human or veterinary medicine.
[108] Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or derivative or solvate thereof with a pharmaceutically acceptable carrier or excipient.
[109] The compounds and compositions according to the invention can be formulated for any route, for example oral, topical or parenteral administration. The compositions can be, for example, in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, powders or liquid preparations such as solvents or suspensions, which are formulated for oral administration or parenteral administration by injection or infusion. It can be formulated in sterile form to:
[110] Tablets and capsules for oral administration may be in unit dosage form, and include conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Tableting lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants such as potato starch; And pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate. Tablets may be coated according to methods well known in the general pharmaceutical practice.
[111] Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be present as a dry product that is reformed with water or other suitable vehicle before use. Such liquid preparations may be conventional additives, for example suspending agents such as sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydroxylated cooking oil; Emulsifiers such as lecithin, sorbitan monooleate or acacia; Non-aqueous vehicles (which may include cooking oil), such as almond oil, oily esters (eg glycerin), propylene glycol or ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And, if desired, conventional flavoring and coloring agents.
[112] Compositions according to the invention for topical administration can be administered, for example, in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, nasal drops, non-spraying agents, infiltration dressings and aerosols, suitable conventional additives For example, preservatives, solvents to aid drug penetration, and emollients in ointments and creams. In addition, such topical preparations may contain compatible conventional carriers, such as cream or ointment bases, ethanol or oleyl alcohols for lotions and aqueous bases for spraying. Such carriers may comprise from about 1% to about 98% by weight of the formulation, more generally up to about 80% by weight of the formulation.
[113] In addition, the compositions according to the invention for topical administration may contain steroidal anti-inflammatory agents, such as betamethasone, in addition to those mentioned above.
[114] The composition according to the invention may be formulated as a suppository, which may contain conventional suppository bases such as cocoa-butter or other glycerides.
[115] Compositions according to the present invention for parenteral administration may conveniently be a single, flowable administration, which may be prepared using the compounds of the present invention and sterile vehicles (preferably water). Depending on the vehicle and concentration used, the compounds of the present invention may be suspended or dissolved in the vehicle. In preparing the solution, the compounds are dissolved in water for injection, filtered and sterilized and then filled into suitable vials or ampoules and then sealed. Advantageously, conventional additives such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To improve the stability of the solution, the composition can be frozen after filling the vial and water is removed under vacuum; The resulting lyophilized powder can then be sealed in a vial, and the vials of accompanying water for injection can be fed to reconstitute the liquid prior to use. Parenteral suspensions can be prepared in substantially the same manner except that the compounds are suspended in the vehicle instead of dissolved and sterilization cannot be achieved by filtration. Instead, it can be sterilized by exposing the compound to ethylene oxide before suspending in the sterile vehicle. Advantageously, surfactants or wetting agents are included in the suspension to promote a uniform distribution of the compound.
[116] The compounds or compositions according to the invention are suitably administered to a patient in an antimicrobial effective amount.
[117] The composition according to the invention may suitably contain 0.001% by weight, preferably 10 to 60% by weight (excluding spray composition) of the compounds according to the invention (based on the total weight of the composition), depending on the method of administration. .
[118] Where the composition according to the invention is present in unit dosage form, eg as a tablet, each unit dosage may comprise 25 to 1000 mg, preferably 50 to 500 mg of the composition according to the invention.
[119] Representative compositions of the present invention include compositions suitable for intranasal administration, in particular compositions reaching the nasal cavity. Such compositions are preferably suitable for focused delivery to the residence in the nasal cavity. The term 'intensive delivery' is used to mean that the composition is delivered into the nasal cavity rather than remaining in the nasal cavity. In the nasal cavity, the term 'residence' is used to mean that a composition once delivered to the nasal cavity remains in the nasal cavity over several hours rather than being washed away immediately or later. Preferred compositions include spray compositions and creams. Representative spray compositions include aqueous compositions as well as oily compositions containing amphiphilic agents that increase viscosity when the composition contacts moisture. Creams, especially creams with a rheology which allows the creams to be easily applied in the nasal cavity, can also be used.
[120] Preferred aqueous spray compositions include, in addition to water, other excipients such as tonicity modifiers such as salts such as sodium chloride; Preservatives such as benzalkonium salts; Surfactants such as nonionic surfactants such as polysorbates; And buffers such as sodium dihydrogen phosphate at low levels, typically less than 1%.
[121] In addition, the pH of the composition can be adjusted for optimal stability of the drug during storage. For compounds of the present invention, the pH is in the range of 5 to 6, preferably about 5.3 to 5.8, usually about 5.5.
[122] Representative oil spray compositions and cream compositions are disclosed in WO 99/07341 and WO 99/12520 (SmithKline Beecham). Representative aqueous spray compositions have already been disclosed in WO 99/21855 (SmithKline Beecham).
[123] Suitably, the drug is present in the composition at 0.001 to 5% by weight, preferably 0.005 to 3% by weight of the composition for intranasal delivery. Amounts of 0.5% to 1% by weight (oily composition and cream) and 0.01 to 0.2% by weight (aqueous composition) of the composition are suitable.
[124] Spray compositions according to the invention can be delivered intranasally by means of spray devices, for example air lift pumps, which are well known in the art for nasal spraying. Preferred devices include devices suitable for intranasal administration by application of a metered and optionally modified nozzle to provide the composition in unit volume, preferably about 100 μl.
[125] The invention is illustrated by the following examples.
[126] Note on the naming of pleuromutin analogs
[127] The systematic name of the compound of formula (a) under the IUPAC system is (1S, 2R, 3S, 4S, 6R, 7R, 8R, 14R) -3,6-dihydroxy-2,4,7,14-tetramethyl -4-vinyl-tricyclo [5.4.3.0 ^1,8 ] tetradecane-9-one. In addition, it is also called mutilin using the species name, H. Berner, G. Schulz and H. Schneider in Tetrahedron, 1981, 37, 915-919 are used.
[128]
[129] (a) IUPAC Numbering
[130]
[131] (a) mutilin numbering
[132] Preparation 1: (2S) -2-dichloroacetoxy-11-O-trifluoroacetyl-mutiline
[133]
[134] (a) formylated derivatives of mutilin
[135] See A.J. Birch, C.W. Holzapfel and R.W. The reaction was carried out similar to that described in Rickards (Tet (Suppl) 1996 8 part III 359.) Mutinine (6 g) in toluene (330 mL) and methyl formate (100 mL) was added to sodium methoxide (3 g). And stirred for 8 h under argon, after adding ice water (100 mL), 2 N HCl (220 mL) was added, the mixture was shaken, separated and the aqueous phase was extracted with ether. After drying and evaporation, the residue was separated by chromatography, eluting with an ethyl acetate / hexane mixture, first, 2-hydroxymethylenemutiline 11,14-diformate (2.33 g) was eluted:
[136]
[137] Second, 2-hydroxymethylenemutiline 11-formate (3.0 g) was eluted:
[138]
[139] Thirdly a mixture (2: 1) of 2-hydroxymethylenemutiline 14-formate and 2-hydroxymethylenemutiline (1.8 g) was eluted.
[140] (b) 2-hydroxymethylenemutiline
[141] A mixture of 2-hydroxymethylene mutiline 11,14-diformate (2.33 g) and [2-hydroxymethylene mutiline 14-formate + 2-hydroxymethylene mutiline] (1.8 g) was prepared using ethanol (30 ML) and treated with 0.5 M KOH in ethanol (60 mL). After 1 hour the solution was diluted with ethyl acetate (200 mL), washed with 2M HCl (120 mL) and water (100 mL), dried and evaporated to give 2-hydroxymethylenemutiline as foam (3.6 g). Got it.
[142]
[143] (c) 2-diazomutiline
[144] A 2-hydroxymethylenemutiline (3.6 g) solution in dichloromethane was cooled to -10 ° C under argon, then treated with triethylamine (4.6 mL) and tosyl azide (3.55 g) and warmed to room temperature. After 6 hours the solution was washed with 0.5 M HCl (150 mL) and water (100 mL), dried and evaporated. 2-diazomutiline was obtained as yellow crystals (1.7 g) from ethyl acetate / hexanes; IR (CHCl ₃ ) 3634, 2082 and 1670 cm ⁻¹ .
[145] (d) (2S) -2-dichloroacetoxymutin
[146] A solution of 2-diazomutiline (1.7 g) in dichloromethane (40 mL) was ice cooled and treated by dropwise addition of dichloroacetic acid (0.5 mL). Thirty minutes after the bath was removed, the solution became colorless. It was washed with aqueous NaHCO ₃ (50 mL), dried and evaporated. Chromatography eluting with 1: 3 ethyl acetate / hexanes gave the title compound as two less polar main products (white foam, 1.6 g).
[147]
[148] (e) (2S) -2-dichloroacetoxy-11-O-trifluoroacetylmutiline
[149] Dichloroacetoxymutiline (5.8 g, 0.012 mol) in anhydrous tetrahydrofuran (120 mL) was treated with trifluoroacetylimidazole (1.54 mL, 0.0135 mol) and stirred at ambient temperature for 18 hours. Ethyl acetate (200 mL) was added to this mixture and washed with dilute sodium chloride solution (2 x 200 mL). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. Chromatography on silica gel eluting with ethyl acetate / hexanes (9: 1) gave the title compound (4.98 g, 71%).
[150]
[151] Preparation 2: 6-tert-butyloxycarbonylaminonicotinic acid
[152]
[153] Methyl-6-aminonicotinate (10 g) in t-butanol (500 mL) was treated with di-tert-butyldicarbonate (15.8 g) and heated at 100 ° C for 36 h. The mixture was concentrated in vacuo. Trituration with diethyl ether gave methyl 6-tert-butyloxycarbonylaminonicotinate (12.8 g). This mixture was treated with lithium hydroxide monohydrate in a mixture of tetrahydrofuran (150 mL) and water (150 mL) for 18 hours, evaporated to a small volume and acidified with citric acid. Filtration gave the title compound as a white solid (8.99 g, 57%). MS (−ve ion chemical ionization) m / z 237 ([M ⁻ H] ⁻ , 80%), 193 (100%).
[154] Preparation 3: 6-tert-butyloxycarbonylaminoisonicotinic acid
[155]
[156] The title compound was prepared in analogy to Preparation 2 from methyl 6-aminoisonicotinate by DJ Stanonis, J. Org. Chem. 22 (1957) 475] was obtained. MS (−ve ion chemical ionization) m / z 237 ([M ⁻ H] ⁻ , 55%), 193 (100%).
[157] Preparation 4: Sodium 5-bis-t-butoxycarbonylaminopyridin-3-ylcarboxylate
[158] (a) ethyl 5-aminonicotinate
[159] 5-aminonicotinic acid (2.2 g) in ethanol (20 mL) [Bachman and Micucci, J. Amer. Chem. Soc. 70 (1948) 2381] were ice cooled, saturated with HCl gas and refluxed for 4 hours. The mixture was concentrated to a small volume and separated between EtOAc (100 mL) and saturated NaHCO ₃ solution (100 mL). The organic phase was further washed with aqueous NaHCO ₃ solution, dried and evaporated to afford the title compound as a white solid (1.34 g). MS (+ ve ion chemical ionization) m / z 167 (MH ⁺ , 100%).
[160] (b) ethyl 5-bis-t-butoxycarbonylaminopyridin-3-yl carboxylate
[161] A solution of ethyl 5-aminonicotinate (1.3 g) in 1,2-dichloroethane (20 mL) was added with triethylamine (2.4 mL), di-t-butyldicarbonate (5.12 g) and 4-dimethylaminopyridine. (14 mg) and refluxed for 1 hour. The solvent was evaporated and the residue was dissolved in EtOAc (50 mL), washed with water (2 x 50 mL), dried and evaporated. Chromatography gave the title compound as a white solid (947 mg). MS (+ ve ion chemical ionization) m / z 367 (M−H ⁺ , 40%), 167 (100%).
[162] (c) sodium 5-bis-t-butoxycarbonylaminopyridin-3-ylcarboxylate
[163] A solution of ethyl 5-bis-t-butoxycarbonylaminopyridin-3-ylcarboxylate (0.9 g) in dioxane (15 mL) / water (1 mL) was treated with 2N NaOH aqueous solution (1.62 mL) and , Stirred overnight. The solution was evaporated to afford the title compound as a solid which was dried under vacuum (0.912 g). MS (+ ve ion chemical ionization) m / z 339 (MH ⁺ free acid, 3%), 167 (100%).
[164] Preparation 5: Sodium 6-bis-t-butoxycarbonylaminopyridin-2-ylcarboxylate
[165] Similar to steps 2 and 3 of Preparation 4 from ethyl 6-aminopyridin-2-ylcarboxylate [Ferrari and Marcon, Farmaco Ed. Sci. 14 (1959) 594-596] The title compounds were prepared in quantitative total yield.
[166]
[167] Preparation 6: Sodium 5-bis-t-butoxycarbonylaminopyridin-2-ylcarboxylate
[168] Similar to steps 2 and 3 of Preparation 4, the reaction was performed from methyl 5-aminopyridin-2-ylcarboxylate [O.P. Shkurko and V.P. Mamaev, Chem. Heterocycl. Compd. 26 (1990) 47-52] The title compound was prepared in a total yield of 52%.
[169]
[170] Preparation 7: Sodium 4-bis-t-butoxycarbonylaminopyridin-2-ylcarboxylate
[171] (a) Methyl 4-aminopyridin-2-ylcarboxylate
[172] Methyl 4-nitropyridin-2-ylcarboxylate (0.7 g) in methanol (30 mL) [Deady et al., Aus. J. Chem. 24 (1971) 385-390] was treated with 10% Pd / C (0.3 g) and stirred overnight under atmospheric nitrogen. The solution was filtered and evaporated to give the title compound (0.55 g).
[173]
[174] (b) and (c) were carried out similarly to steps (b) and (c) of Preparation 4 to give the sodium salt of the title compound in a total yield of 67%. MS (−ve ion chemical ionization) m / z 337 ([M ⁻ H] ⁻ free acid, 70%), 178 (100%).
[175] Preparation 8: Sodium 6-methoxynicotinate
[176] The title compound was prepared by hydrolysis of methyl 6-methoxynicotinate in a similar manner to step (c) of Preparation 4.
[177] Preparation 9: 2-t-butoxycarbonylaminothiazole-5-carboxylic acid
[178] (a) Methyl 2-bis-t-butoxycarbonylaminothiazole-5-carboxylate
[179] A solution of methyl 2-aminothiazole-5-carboxylate (2.3 g) in dichloromethane (60 mL) was prepared by [R. Noto, M. Ciofalo, F. Buccheri, G. Werber and D. Spinelli, JCS Perkin Trans. 2, (1991) 349-352] Treated with triethylamine (2 mL), catalytic amount of 4-dimethylaminopyridine and di-t-butyldicarbonate (8 g) and stirred overnight. The solution was evaporated to small volume, added to silica column and eluted with ethyl acetate / hexanes to give the title compound (3.56 g).
[180] (b) 2-t-butoxycarbonylaminothiazole-5-carboxylic acid
[181] A solution of methyl 2-bis-t-butoxycarbonylaminothiazole-5-carboxylate (3.56 g) in dioxane (50 mL) was treated with 2N NaOH solution (9 mL) and stirred for 1 hour. Further treated with 17 mL of 2N NaOH and stirred for 1 hour more. 2 N HCl was used to bring the mixture to pH 8 and evaporated. The solid was dissolved in water (10 mL), treated with a solution of citric acid (6.6 g) in water (20 mL) and extracted with ethyl acetate (30 mL). Ethyl acetate was separated, washed with water (3 x 20 mL), dried and evaporated to afford the title compound as a solid (0.96 g).
[182]
[183] Preparation 10: 2-t-butoxycarbonylaminothiazole-4-carboxylic acid
[184] (a) ethyl 2-aminothiazole-4-carboxylate
[185] 2-aminothiazole-4-carboxylic acid hydrobromide (10 g) in ethanol (35 mL) [EC Roberts and YF Shealy, J. Med. Chem. 15 (1972) 1310-1312 were treated with concentrated sulfuric acid and refluxed for 48 hours. The solution was evaporated to 25% of the initial volume and water (20 mL) was added. NaHCO ₃ was added to basify, the solid was filtered off, washed with water and dried under vacuum to afford the title compound (5.64 g).
[186]
[187] (b) and (c) were carried out similarly to steps (b) and (c) of Preparation 9 to obtain the acid of the title compound.
[188]
[189] Preparation 11: Sodium 2,6-bis (bis-t-butoxycarbonylamino) pyrimidine-4-carboxylate
[190]
[191] (a) Methyl 2,6-diaminopyrimidine-4-carboxylate
[192] 2,6-diamino pyrimidine-4-carboxylic acid using the method of step (a) in Preparation 4 [G.D. Davies, F. Baiocchi, R.K. Robins and C.C. Cheng, J. Org. Chem 26 (1961) 2755-2759] was esterified with HCl / MeOH to give a yield of 100%.
[193]
[194] (b) was carried out analogously to step (a) of preparation 9 and (c) was carried out similarly to step ( c) of preparation 4 to give the title compound (30% over 2 steps).
[195]
[196] Preparation 12: 2- (1-t-butoxycarbonylpiperidin-4-yl) thiazole-4-carboxylic acid
[197]
[198] A solution of ethyl 2- (1-t-butoxycarbonylpiperidin-4-yl) thiazole-4-carboxylate (from Tripos UK Ltd) in dioxane (5 mL) / water (1 mL) was added. Treated with N NaOH (0.6 mL) and left overnight. The solution was diluted with EtOAc (20 mL) and 1 M citric acid solution (10 mL), shaken and separated. The organic phase was washed with water (3 x 10 mL), dried and evaporated to afford the title compound as a solid (295 mg). MS (+ ve ion electrospray) m / z 335 (MNa ⁺ , 30%), 239 (100%); (-ve ion electrospray) m / z 267 ([M-COOH] ⁻ , 100%).
[199] Preparation 13: 2-methoxypyrimidine-5-carboxylic acid
[200] Methyl 2-methoxypyrimidine-5-carboxylate (944 mg) in dioxane (33 mL) / water (33 mL) [Z. Budesinsky and J. Vavrina, Collect. Czech. Chem. Commun. 37 (1972) 1721-1733] was treated with 2 N NaOH (3.37 mL), left overnight and evaporated to a small volume. The residue was dissolved in water (30 mL) and 2N HCl was added to adjust the pH to 2 and the mixture was extracted with EtOAc (4 x 30 mL). EtOAc was dried and evaporated to afford the title compound as a white solid (605 mg).
[201]
[202] Preparation 14: (2S) -2-dichloroacetoxy-19,20-dihydro-11-O-trifluoroacetylmutiline
[203] 2-diazo-19,20-dihydromutillin [H. Berner, G. Schulz and G. Fischer, Monatsh. fuer Chemie, 112 (1981) 1441-1450] was treated as in steps (d) and (e) of Preparation 1 to obtain the title compound. MS (−ve ion electrospray) m / z 603 (MOAc ⁻ , 65%), 543 ([M ⁻ H] ⁻ , 100%).
[204] Preparation 15: Sodium 2-bis-t-butoxycarbonylaminopyrazine-5-carboxylate
[205]
[206] Ethyl 2-aminopyrazine-5-carboxylate [E. Felder, D. Pitre and E.B. Grabitz, Helv. Chim. Acta 47 (1964) 873-876 was treated similarly to step (b) of Preparation 9 and then to step (c) of Preparation 4 to give the title compound as a white solid.
[207]
[208] Preparation 16: Sodium 2-N-t-butoxycarbonyl-N-methylaminopyrimidine-5-carboxylate
[209]
[210] 2-N-methylaminopyrimidine-5-carboxylic acid [D.J. Brown and M.N. Paddon-Row, J. Chem. Soc. C, (1966) 164-166, were esterified using the method of step (a) of Preparation 4. The ester was treated according to step (a) of Preparation 9 and then step (c) of Preparation 4 to afford the title compound.
[211]
[212] Preparation 17: Sodium 5-bis-t-butoxycarbonylamino-6-methoxynicotinate
[213]
[214] Methyl 5-amino-6-methoxynicotinate [Morisawa et al., Agric. Biol. Chem. 40, (1976) 101 were processed according to step (a) of Preparation 9 and then step (c) of Preparation 4 to afford the title compound. MS (−ve ion chemical ionization) m / z 367 ([M ⁻ H] ⁻ , 100%).
[215] Preparation 18: Sodium 6-bis-t-butoxycarbonylamino-5-methoxynicotinate
[216]
[217] (a) Methyl 6-amino-5-methoxynicotinate
[218] 2-amino-5-bromo-3-methoxypyridine (7 g) in methanol (35 mL) [den Hertog et al., Recl. Trav. Chim. Pays-Bas, 74 (1955), 1171], added 80 psi of carbon monoxide to a mixture of bis (triphenylphosphine) palladium dibromide (3.5 g) and tri-n-butylamine (9 mL), and 16 at 112 ° C. Heated for hours. The mixture was cooled, evaporated and the residue was chromatographed to elute with 1: 1 EtOAc / hexanes to give the title compound (2.32 g). MS (+ ve ion chemical ionization) m / z 183 (MH ⁺ , 100%).
[219] (b) and (c) were carried out similarly to step (a) of Preparation 9 and (c) of Preparation 4 to give sodium 6-bis-t-butoxycarbonylamino-5-methoxynicotinate (total 77%). MS (−ve ion chemical ionization) m / z 367 ([M ⁻ H] ⁻ , 100%).
[220] Preparation 19: Sodium 6-bis-t-butoxycarbonylamino-5-nitronicotinate
[221]
[222] 6-amino-5-nicotinic acid [Marckwald, Chem. Ber. 27, (1984), 1336] were esterified by the method of step (a) of preparation 4, N-protected as described in step (a) of preparation 9, and estered by the method of step (c) of preparation 4 Hydrolysis gave the title compound.
[223]
[224] Preparation 20: Sodium 2-bis-t-butoxycarbonylamino-6-methoxypyrimidine-4-carboxylate
[225]
[226] (a) Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate
[227] Methyl 2,6-dichloropyrimidine-4-carboxylate (10 g) in methanol (100 mL) [M. Winn et al., J. Med. Chem. 36 (18) (1993) 2676-2688] were treated with sodium ethoxide (3 g) and left for 16 hours. Methanol was evaporated and the residue was separated with dichloromethane and saturated aqueous NaHCO ₃ . The organic phase was washed with brine, dried and evaporated to afford the title compound (24%).
[228]
[229] (b) sodium 2-chloro-6-methoxypyrimidine-4-carboxylate
[230] Methyl ester (a) was hydrolyzed according to step (c) of Preparation 4 to give the title compound (100%).
[231]
[232] (c) methyl 2-amino-6-methoxypyrimidine-4-carboxylate
[233] A solution of sodium 2-chloro-6-methoxypyrimidine-4-carboxylate (2 g) in concentrated aqueous ammonia solution (30 mL) was refluxed for 4 hours and evaporated to dryness. The residue was dissolved in methanol (200 mL), treated with concentrated sulfuric acid (1 mL) and refluxed for 16 h. After evaporation to a small volume, the mixture was separated with EtOAc and saturated aqueous NaHCO ₃ solution. The organic phase was washed with brine, dried and evaporated to afford the title compound as a white solid (700 mg).
[234]
[235] (d) sodium 2-bis-t-butoxycarbonylamino-6-methoxypyrimidine-4-carboxylate
[236] The aminopyrimidine (c) was protected according to the method of step (b) of preparation 4 and ester hydrolyzed according to the method of step (c) of preparation 4 to give the title compound.
[237] Preparation 21: Sodium 2-bis-t-butoxycarbonylaminopyrimidin-4-ylcarboxylate
[238]
[239] The title compound was prepared from 2-aminopyrimidine-4-carboxylic acid similarly to Preparation 4 [T. Matsukawa, K. Shirakawa, J. Pharm. Soc. Japan (1952), 72, 909-912.
[240]
[241] Preparation 22: 6-N-t-butoxycarbonyl-N-methylaminonicotinic acid
[242]
[243] (a) 6-methylaminonicotinic acid hydrochloride
[244] 6-Chloronicotinic acid (4.5 g) was dissolved in methanol (50 mL), treated with 33% methylamine (25 mL) in ethanol solution and heated in a sealed cylinder at 140 ° C. for 18 h. The mixture was cooled and evaporated to dryness. Trituration with 1: 1 methanol / diethyl ether gave the title compound (3.7 g, 69%). MS (+ ve is electrospray) m / z 153 (MH ⁺ , 100%).
[245] (b) methyl (6-methylaminonicotinate)
[246] 6-Methylaminonicotinic acid hydrochloride (3.65 g) in methanol (100 mL) was treated with concentrated sulfuric acid (2 mL) and heated to reflux for 18 h. The mixture was evaporated to dryness and the residue was separated with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried and evaporated to dryness to afford the title compound (1.07 g). MS (+ ve ion electrospray) m / z 167 (MH ⁺ , 100%).
[247] (c) Methyl 6-N-t-butoxycarbonyl-N-methylamino nicotinate
[248] The title compound was prepared similar to step (b) of Preparation 4 (1.41 g, 58%).
[249] (d) 6-N-t-butoxycarbonyl-N-methylaminonicotinic acid
[250] Ester hydrolysis was carried out analogously to the ester hydrolysis of Preparation 2 to give the title compound (76%). MS (−ve ion chemical ionization) m / z 251 ([M ⁻ H] ⁻ , 100%).
[251] Preparation 23: Sodium 3- (N-t-butoxycarbonyl-N-methylamino) pyridazine-6-carboxylate
[252]
[253] (a) 3-methylaminopyridazine-6-carboxylic acid
[254] 3-chloropyridazine-6-carboxylic acid (2.5 g) [RF Homer, H. Gregory, WG Overend and LF Wiggins, J. Chem. Soc (1948) 2195-9] was treated with 8 M methylamine (2.16 mL) in ethanol and heated to 100 ° C. for 18 h in a sealed bomb. The solution was acidified to pH 4 with 5 N HCl and the precipitate was filtered to give the title compound (0.58 g). MS (−ve ion chemical ionization) m / z 152 ([M ⁻ H] ⁻ , 100%).
[255] (b) ethyl 3-methylaminopyridazine-6-carboxylate
[256] A solution of 3-methylaminopyridazine-6-carboxylic acid (0.58 g) in ethanol (50 mL) was saturated with HCl gas, refluxed for 48 hours, and evaporated. The residue was separated with EtOAc and aqueous NaHCO ₃ solution and the aqueous phase was reextracted with EtOAc. The organic phase was dried and evaporated to give the title compound (0.61 g). MS (+ ve ion chemical ionization) m / z 182 (MH ⁺ , 100%).
[257] (c) ethyl 3- (N-t-butoxycarbonyl-N-methylamino) pyridazine-6-carboxylate
[258] Prepared similarly to step (a) of Preparation 9 (72%). MS (+ ve ion chemical ionization) m / z 282 (MH ⁺ , 100%).
[259] (d) sodium 3- (N-t-butoxycarbonyl-N-methylamino) pyridazine-6-carboxylate
[260] Prepared similarly to step (c) of preparation 4 (93%). MS (−ve ion chemical ionization) m / z 252 ([M ⁻ H] ⁻ , 100%).
[261] Preparation 24: Sodium 6- (bis-t-butoxycarbonylamino) -5-cyanonicotinate
[262]
[263] (a) 6-hydroxy-5-iodonicotinic acid
[264] 6-hydroxynicotinic acid (20 g) in water (200 mL) and H ₂ SO ₄ (80 mL) was heated to 90 ° C for 1 h. Both potassium iodide (0.42 equiv) and sodium iodide (0.96 equiv) were added dropwise over 2 hours. After 1 hour more the mixture was cooled to 90 ° C. to 60 ° C. and 1 kg of ice was added. The brown solid was filtered off, dried and dissolved in DMF (30 mL) / EtOH (1 liter). Sodium metabisulphite was added until brown disappeared, the mixture was poured on ice (2 kg), 1.5 liters of water was added and the white solid filtered off to give the title compound (16.5 g).
[265]
[266] (b) methyl 6-chloro-5-iodonicotinate
[267] 6-hydroxy-5-iodonicotinic acid (15.25 g) was refluxed in thionyl chloride (40 mL) / DMF (5 mL) for 4 h, cooled and evaporated to dryness. The residue was dissolved in chloroform (50 mL) and added to methanol (100 mL). Evaporation gave the title compound (17 g).
[268]
[269] (c) sodium 6-chloro-5-iodonicotinate
[270] Prepared similarly to step (c) of preparation 4 (100%).
[271] NMR δ (DMSO) 8.72 (1 H, d), 8.59 (1 H, d).
[272] (d) methyl 6-amino-5-iodonicotinate
[273] Sodium 6-chloro-5-iodonicotinate (5 g) in 0.88 ammonia solution (125 mL) was heated to 150 ° C. for 18 h in a sealed bomb, cooled and evaporated to dryness. The residue was esterified according to the method of step (b) of preparation 22 (2.44 g). MS (−ve ion chemical ionization) m / z 277 ([M ⁻ H] ⁻ , 100%).
[274] (e) Methyl 6-amino-5-cyanonicotinate
[275] Methyl 6-amino-5-iodonicotinate (2.44 g) in dioxane (50 mL), tris (dibenzylideneacetone) dipalladium (0) (4% by weight), 1,1'-bis (diphenyl A mixture of phosphino) ferrocene (16% by weight) and copper cyanide (4 equiv) was refluxed for 4 hours, cooled and filtered. The filtrate was evaporated and the residue was treated by chromatography eluting with 4% MeOH / CH ₂ Cl ₂ to afford the title compound (1.45 g).
[276]
[277] (f) Methyl 6- (bis-t-butoxycarbonylamino) -5-cyanonicotinate
[278] Prepared similarly to step (a) of Preparation 9 (73%).
[279]
[280] (g) sodium 6- (bis-t-butoxycarbonylamino) -5-cyanonicotinate
[281] Prepared similarly to step (c) of preparation 4 (100%).
[282]
[283] Pyridine-5-carboxylic acid is described in I.T. Forbes, R. T. Martin and G.E. Jones, Preparation of indolylurea derivatives as antagonists, PCT Int. Appl. (1993) WO9318028 A1 19930916.
[284] 2-dimethylaminopyrimidine-5-carboxylic acid is described in P. Dorigo, D. Fraccarollo, G. Santostasi, I. Maragno and M. Floreani, J. Med. Chem. 39 (1996) 3671-3683.
[285] Pyrazolo [1,5-a] pyrimidine-3-carboxylic acid was obtained from Cambridge.
[286] 6-dimethylaminonicotinic acid is described in Tschitschibabin et al., Chem. Ber. (1929), 62, 3052].
[287] 3-Chloropyridazine-6-carboxylic acid is described in R.F. Homer, H. Gregory, W.G.Overend and L.F. Wiggins, J. Chem. Soc. (1948), 2195-2199.
[288] Example 1 (6-Amino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester
[289]
[290] (a) (6-tert-butyloxycarbonylamino-3-pyridinylcarbonyl) carbamic acid-2- (S) -2-dichloroacetoxymutin 14-ester-11-trifluoroacetate
[291]
[292] 6-tert-butyloxycarbonylaminonicotinic acid (1.0 g) in dichloromethane (100 mL) was treated with oxalyl chloride (0.44 mL) and dimethylformamide (1 drop) and stirred at ambient temperature for 3 hours. Evaporation to dryness afforded an acid chloride, which was dissolved in dichloromethane (150 mL), silver cyanate (1.0 g, 6.7 mmol), 2- (S) -2-dichloroacetoxymutin 11-trifluoroacetate ( 2.3 g) and triethylamine (0.65 mL) and stirred at ambient temperature for 18 hours. After filtration and evaporation to dryness of the filtrate, the title compound was obtained as a white foam (0.53 g, 15%) by chromatography on silica gel eluting with 25% ethyl acetate in hexane.
[293] (b) (6-tert-butyloxycarbonylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[294]
[295] (6-tert-butyloxycarbonylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -2-dichloroacetoxy-mutiline 14-ester-11-trifluoro in anhydrous ethanol (20 mL) Acetate (0.52 g) was treated with 0.5 N potassium hydroxide (2.5 mL, 1,2 mmol) in ethanol solution and stirred at ambient temperature for 4 hours. The mixture was evaporated to dryness and the residue was separated between water and ethyl acetate. The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness to afford the title compound (0.37 g, 100%).
[296] (c) (6-Amino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[297]
[298] (6-tert-butyloxycarbonylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutiline 14-ester (0.37 g) in dichloromethane (50 mL) was treated with trifluoroacetic acid ( 2 ml) and stirred at ambient temperature for 5 hours. The mixture was evaporated to dryness and the residue was separated into 10% potassium carbonate solution and 10% methanol / dichloromethane (2 x 100 mL). The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. Chromatography on silica gel eluting with 8% methanol / dichloromethane gave the title compound as a white solid (0.117 g, 37%). MS (−ve ion electrospray) m / z 498 ([M ⁻ H] ⁻ , 30%), 161 (100%).
[299] Examples 2 to 27
[300] (a) The following compounds were prepared analogously to step (a) of Example 1.
[301]
[302]
[303]
[304] The 2-aminopyrimidin-5-ylcarbonyl chloride hydrochloride of Example 10 was prepared as 2-aminopyrimidin-5-yl carboxylic acid (0.4 g) in thionyl chloride (20 mL) [P. Schenone et al., J. Heterocyclic Chem. 27 (1990) 295] was refluxed for 4 hours and then evaporated to dryness.
[305] Example 3:
[306] (b) (5-bis-t-butoxycarbonylaminonicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[307] (5-bis-t-butoxycarbonylaminonicotinoyl) carbamic acid 2- (S) -dichloroacetoxymutin 14-ester-11-trifluoroacetate (0.25 g) in ethanol (25 mL) Treated with saturated aqueous NaHCO ₃ (25 mL) and stirred vigorously for 2.5 h. The mixture was diluted with EtOAc (150 mL) and water (150 mL), shaken and separated. The organic phase was dried and evaporated to afford the title compound as a white solid (0.198 g). MS (−ve ion electrospray) m / z 698 ([M ⁻ H] ⁻ , 100%).
[308] Examples 2, 4 to 17, 19 to 21 and 24 to 26
[309] (b) The following compounds were prepared analogously to step (b) of Example 1 or Example 3.
[310]
[311]
[312]
[313] Example 3:
[314] (c) (5-Aminonicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[315] (5-bis-t-butoxycarbonylaminonicotinoyl) carbamic acid 2- (S) -hydroxymutillin 14-ester (0.198 g) in trifluoroacetic acid (2 mL) was left for 1 hour And evaporated. The residue was treated with EtOAc (10 mL) and saturated aqueous NaHCO ₃ (10 mL), shaken and separated. The organic phase was dried and evaporated. Chromatography (EtOAc / MeOH) gave the title compound (0.084 g). MS (−ve ion electrospray) m / z 498 ([M ⁻ H] ⁻ , 100%).
[316] Examples 2, 4-6, 8-9, 11-12, 15, 20-21, 24 and 26
[317] (c) The following compounds were prepared analogously to step (c) of Example 1 or Example 3.
[318]
[319]
[320]
[321] Example 18: (2-N-methylaminopyrimidin-5-ylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester
[322] (b) (2-N-methylaminopyrimidin-5-ylcarbonyl) carbamic acid 2- (S) -dichloroacetoxy-11-O-trifluoroacetylmutiline 14-ester
[323] The BOC-protected material (see table) from step (a) was deprotected with TFA (100%) using the method of step (c) of example 3. MS (−ve ion electrospray) m / z 719 ([M ⁻ H] ⁻ , 100%).
[324] (c) (2-N-methylaminopyrimidin-5-ylcarbonyl) carbamic acid 2- (S) -hydroxymutiline 14-ester
[325] The material from step (b) was treated according to the method of step (b) of Example 3 to give the title compound (64%). MS (+ ve ion electrospray) m / z 515 (MH ⁺ , 100%).
[326] Example 22 (b): (6-Amino-5-nitronicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[327]
[328] (6-Bis-t-butoxycarbonylamino-5-nitronicotinoyl) carbamic acid 2- (S) -dichloroacetoxy-11-O-trifluoroacetylmutylline (see table) Treatment with TFA according to step (c) of, followed by treatment with base according to step (b) of Example 3 gave the title compound (95%). MS (−ve ion chemical ionization) m / z 543 ([M ⁻ H] ⁻ , 100%).
[329] Example 23 (b): (2-amino-6-methoxypyrimidin-4-ylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[330]
[331] (2-bis-t-butoxycarbonylamino-6-methoxypyrimidin-4-ylcarbonyl) carbamic acid 2- (S) -dichloroacetoxy-11-O-trifluoroacetylmutylline (Table Treatment with TFA according to step (c) of Example 3 followed by base according to step (b) of Example 3 to obtain the title compound. MS (−ve ion electrospray) m / z 529 ([M ⁻ H] ⁻ , 60%), 193 (100%).
[332] Example 27: (3-Amino-6-pyridazinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester hydrochloride
[333]
[334] (b) (tetrazole [1,5-b] pyridazine-6-ylcarbonylcarbamic acid (2S) -2-dichloroacetoxy-11-O-trifluoroacetylmutinine 14-ester
[335]
[336] 1- (3-Chloro-6-pyridazinylcarbonyl) carbamic acid (2S) -2-dichloroacetoxy-11-O-trifluoroacetyl mutiline 14-ester at ambient temperature (see table) (1.5 g ) Was treated with sodium azide (0.162 g) in DMF (20 mL) for 4 hours to prepare the title compound. The mixture was then evaporated to dryness, the residue extracted with ethyl acetate (50 mL), washed with water (3 x 50 mL), dried and evaporated to give compound (1.02 g, 70%). MS (−ve ion electrospray) m / z 731 ([M ⁻ H] ⁻ , 15%), 164 (100%).
[337] (c) (3-triphenylphosphoranylideneamino-6-pyridazinyl carbonyl) carbamic acid (2S) -2-dichloroacetoxy-11-O-trifluoroacetylmutinine 14-ester
[338]
[339] (Tetrazolo [1,5-b] pyridazine-6-ylcarbonyl) carbamic acid- (2S) -2-dichloroacetoxy-11-O-trifluoroacetylmutiline 14-ester (0.45 g) Heated to 110 ° C. for 18 h in chlorobenzene (10 mL) with triphenyl-phosphine (0.165 g). After evaporation, the title compound (0.255 g, 43%) was obtained by chromatography on silica gel eluting with 50% ethyl acetate in hexane. MS (+ ve ion electrospray) m / z 967 (MH ⁺ , 80%), 839 (100%).
[340] (d) (3-amino-6-pyridazinylcarbonyl) carbamic acid- (2S) -2-dichloroacetoxy-11-O-trifluoroacetylmutinine 14-ester
[341]
[342] (3-Triphenylphosphoranylideneamino-6-pyridazinylcarbonyl) carbamic acid- (2S) -2-dichloroacetoxy-11-O-trifluoroacetylmutyline 14-ester (0.25 g) Treated with glacial acetic acid (5 mL) and water (0.5 mL) and heated at 100 ° C. for 1 h. The mixture is evaporated to dryness and the residue is extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried and evaporated to dryness to give the title compound 1: 1 mixture with triphenylphosphine oxide (0.23 g, 88%). Got it. MS (−ve ion electrospray) m / z 705 ([M ⁻ H] ⁻ , 18%), 375 (100%).
[343] (e) (3-amino-6-pyridazinylcarbonyl) carbamic acid- (2S) -2-hydroxymutinine 14-ester hydrochloride
[344] (3-Amino-6-pyridazinylcarbonyl) carbamic acid- (2S) -2-dichloroacetoxy-11-O-trifluoro acetyl mutilin 14-ester (0.23 g) was prepared in Example 3 ( Treatment with an aqueous sodium bicarbonate solution as in b) followed by ethereal hydrogen chloride gave the title compound (0.05 g, 41%). MS (−ve ion electrospray) m / z 499 ([M ⁻ H] ⁻ , 100%).
[345] Example 28: (3-N-methylpyridazine-6-ylcarbonyl) carbamic acid 2- (S) -hydroxymutiline 14-ester
[346] (b) (3-N-methylpyridazine-6-ylcarbonyl) carbamic acid 2- (S) -dichloroacetoxy-11-O-trifluoroacetylmutiline 14-ester
[347] The BOC-protected material from step (a) (see table) was deprotected with TFA using the method of step (c) of example 3 (73%). MS (−ve ion electrospray) m / z 720 ([M ⁻ H] ⁻ , 100%).
[348] (c) (3-N-methylpyridazine-6-ylcarbonyl) carbamic acid 2- (S) -hydroxymutiline 14-ester
[349] The material from step (b) was treated according to the method of step (b) of Example 3 to give the title compound (44%). MS (−ve ion electrospray) m / z 513 ([M ⁻ H] ⁻ , 100%).
[350] Example 29: (6-Amino-5-cyanonicotinoyl) carbamic acid 2- (S) -hydroxymutillin 14-ester
[351] (b) (6-amino-5-cyanonicotinoyl) carbamic acid 2- (S) -dichloroacetoxy-11-O-trifluoroacetylmutinine 14-ester
[352] The BOC-protected material from step (a) (see table) was deprotected with TFA using the method of step (c) of example 3 (76%). MS (−ve ion electrospray) m / z 729 ([M ⁻ H] ⁻ , 100%).
[353] (c) (6-Amino-5-cyanonicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester
[354] The material from step (b) was treated according to the method of step (b) of example 3 to give the title compound (60%). MS (−ve ion electrospray) m / z 523 ([M ⁻ H] ⁻ , 100%).
[355] Example 30: [2- (1-Carboxamidomethylpiperidin-4-yl) thiazole-4-carbonyl] carbamic acid 2- (S) -hydroxymutinine 14-ester
[356]
[357] [2- (Piperidin-4-yl) thiazole-4-carbonyl] carbamic acid 2- (S) -hydroxymutillin 14-ester in acetonitrile (3.5 mL) / DMF (0.5 mL) Example 12, 120 mg) was treated with potassium carbonate (73 mg) and 2-bromoacetamide (29 mg) and stirred overnight. The mixture was diluted with EtOAc (10 mL), washed with water (3 x 10 mL), dried and evaporated. The title compound (90 mg) was obtained by chromatography eluting with chloroform / methanol / 0.88NH ₃ (aq) 94: 6: 0.6. MS (+ ve ion electrospray) m / z 631 (MH ⁺ , 30%), 269 (100%).
[358] Example 31: [2- (1-Cyanomethylpiperidin-4-yl) thiazole-4-carbonyl] carbamic acid 2- (S) -hydroxymutillin 14-ester
[359] Using the bromoacetonitrile as the alkylating agent, the title compound (74%) was obtained by a reaction similar to that of Example 30. MS (−ve ion electrospray) m / z 611 ([M ⁻ H] ⁻ , 100%).
[360] Example 32: (6-Aminopyridin-2-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[361]
[362] A solution of (6-aminopyridin-2-ylcarbonyl) carbamic acid 2 (S) -hydroxymutinine 14-ester (Example 4) (150 mg) in ethanol (20 mL) was added with 10% Pd / C ( 50 mg) and stirred overnight under hydrogen at atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated to afford the title compound (130 mg). MS (+ ve ion electrospray) m / z 502 (MH ⁺ , 40%), 524 (MNa ⁺ , 65%), 565 (100%).
[363] Example 33: (6-Amino-5-cyanonicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[364] (6-Amino-5-cyanonicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester was hydrogenated according to the method of Example 32 (but using dioxane instead of EtOH as solvent). The title compound (62%) was obtained. MS (−ve ion electrospray) m / z 525 ([M ⁻ H] ⁻ , 100%).
[365] Example 34: (3-oxo-3,4-dihydropyrido [2,3-b] pyrazine-7-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymu Tilin 14-ester
[366]
[367] (a) (5,6-Diaminonicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[368] (6-Amino-5-nitronicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester (Example 22) was hydrogenated according to the method of Example 32 to give the title compound (86%). . MS (+ ve ion chemical ionization) m / z 517 (MH ⁺ , 100%).
[369] (b) (3-oxo-3,4-dihydropyrido [2,3-b] pyrazine-7-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutiline 14-ester
[370] A solution of (5,6-diaminonicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester (118 mg) in ethanol (10 mL) was ethylglyoxylate (150 mL in 4.9 M toluene solution) solution and heated to 50 ° C. for 3 h. The solvent was evaporated and the residue was chromatographed to elute with dichloromethane / methanol 97: 3 to give the title compound (13 mg). MS (+ ve ion chemical ionization) m / z 555 (MH ⁺ , 100%).
[371] Example 35: (2-Aminothiazole-5-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester
[372]
[373] (a) (2-t-butoxycarbonylaminothiazole-5-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[374] (2-t-butoxycarbonylaminothiazole-5-ylcarbonyl) carbamic acid-2- (S) -hydroxymutinine 14-ester (Example 8, step (b)) was added to Example 32. Hydrogenation as described gave the title compound (46%). MS (−ve ion electrospray) m / z 606 ([M ⁻ H] ⁻ , 50%), 268 (100%).
[375] (b) (2-aminothiazole-5-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[376] The BOC-protected compound from step (a) was deprotected as described in step (c) of Example 3 to give the title compound (46%). MS (−ve ion electrospray) m / z 506 ([M ⁻ H] ⁻ , 100%).
[377] Example 36: (5-Amino-6-methoxynicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[378]
[379] (5-Amino-6-methoxynicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester was hydrogenated as described in Example 32 to afford the title compound. MS (−ve ion electrospray) m / z 530 ([M ⁻ H] ⁻ , 50%), 192 (100%).
[380] Examples 37-39
[381] (a) analogous to step (a) of Example 1 using 2- (S) -2-dichloroacetoxy-19,20-dihydro-11-O-trifluoroacetylmutiline (preparation 14) The following compounds were prepared.
[382]
[383]
[384] Example 37 (b): (2-Methylaminopyrimidine-5-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester
[385]
[386] (2-Nt-butoxycarbonyl-N-methylaminopyrimidin-5-ylcarbonyl) carbamic acid 2- (S) -dichloroacetoxy-19,20-dihydro-11-O-trifluoroacetyl The mutiline 14-ester (see table) was treated with TFA according to the method of step (c) of example 3 and then (100%) [MS (-ve ion electrospray) m / z 721 ([M ⁻ H] ⁻ , 100%)], followed by the method according to the method of step (b) of example 3 (44%) [MS (-ve ion electrospray) m / z 515 ([MH] ⁻ , 100%)].
[387] Example 38 (b): (2-methoxypyrimidine-5-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester
[388]
[389] (2-methoxypyrimidin-4-ylcarbonyl) carbamic acid 2- (S) -dichloroacetoxy-19,20-dihydro-11-O-trifluoroacetylmutiline 14-ester Deprotection was carried out in accordance with the method of step (b) to afford the title compound (43%). MS (+ ve ion electrospray) m / z 518 (MH ⁺ , 100%)
[390] Example 39 (b): (6-aminonicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester
[391]
[392] (6-t-Butoxycarbonylaminonicotinoyl) carbamic acid 2- (S) -dichloroacetoxy-19,20-dihydro-11-O-trifluoroacetylmutinine 14-ester (see table) Was deprotected according to the method of step (b) of Example 3 (65%) [MS (-ve ion chemical ionization) m / z 600 ([M ⁻ H] ⁻ , 100%)], followed by Example 3 deprotection according to (c) (39%). MS (−ve ion electrospray) m / z 500 ([M ⁻ H] ⁻ , 100%).
[393] Biological data
[394] Compounds of the invention were evaluated for antimicrobial activity by conventional MIC assays for various pathogens.
[395] MICs of 4 μg / ml or less for Staphylococcus aureus Oxford, Streptococcus pneumoniae 1629, Moraxella catarrhalis Ravasio and Haemophilus influenza Q1 in Examples 1-39 Appeared.
[396] Antishanged stability of 2S-hydroxy compounds was measured using human liver granule formulations. Thus, for compounds wherein R ¹ is 2-amino-4-pyridyl and R ² is vinyl, the intrinsic clearance (CLi, metabolic rate measurement) in the presence of human liver granules is 2α-H, CLi> 50 ml / Min / liver g; 2α-OH, CLi = 6.5 ml / min / liver g.

权利要求:
Claims (11)
[1" claim-type="Currently amended] A compound of formula (I)
<Formula I>

In the formula,
R ¹ is a 5- or 6-membered optionally substituted heteroaryl group;
R ² is vinyl or ethyl.
[2" claim-type="Currently amended] 2. A 5 or 6 membered ring according to claim 1, wherein R ¹ comprises 1 or 2 nitrogen atoms and optionally comprises a further heteroatom selected from oxygen or sulfur; Or a 5 or 6 membered ring containing 3 nitrogen atoms; Or a 5 or 6 membered ring comprising 1 or 2 nitrogen atoms fused to a benzene ring or another optionally substituted 5 or 6 membered heteroaryl ring containing 1 or 2 nitrogen atoms.
[3" claim-type="Currently amended] The compound according to claim 1 or 2, wherein R ¹ is pyridine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4 Triazole, benzimidazole, 3-oxo-3,4-dihydropyrido [2,3-b] pyrazine or pyrazolo [1,5-a] pyrimidine.
[4" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 3, wherein R ¹ comprises pyridine, pyrimidine and thiazole.
[5" claim-type="Currently amended] 5. The substituent of claim ¹ , wherein the substituent of R ¹ is amino, mono- or di- (C _1-6 ) alkylamino, (C _1-6 ) alkyl, (C _1-6 ) A compound of formula I selected from alkoxy, nitro and N-containing heterocyclyl.
[6" claim-type="Currently amended] The method of claim 1,
(6-Amino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
(5-Aminonicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester;
(2-N-methylaminopyrimidin-5-ylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
(3-amino-6-pyridazinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
(3-N-methylpyridazine-6-ylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
(6-amino-5-cyanonicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester;
[2- (1-Carboxamidomethylpiperidin-4-yl) thiazole-4-carbonyl] carbamic acid 2- (S) -hydroxymutillin 14-ester;
[2- (1-cyanomethylpiperidin-4-yl) thiazole-4-carbonyl] carbamic acid 2- (S) -hydroxymutinine 14-ester;
(6-Aminopyridin-2-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester;
(6-amino-5-cyanonicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester;
(3-oxo-3,4-dihydropyrido [2,3-b] pyrazine-7-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester ;
(2-aminothiazole-5-ylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester;
(5-amino-6-methoxynicotinoyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester;
(6-amino-5-nitronicotinoyl) carbamic acid 2- (S) -hydroxymutinine 14-ester;
(2-amino-6-methoxypyrimidin-4-ylcarbonyl) carbamic acid 2- (S) -hydroxymutyline 14-ester; And
R ² is ethyl and R ¹ is

A compound of formula I selected from the group consisting of compounds of formula I selected from
[7" claim-type="Currently amended] The method of claim 1,
(5-Amino-6-methoxy-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutillin 14-ester;
(5-Amino-6-methoxy-3-pyridinylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutinine 14-ester;
(6-Amino-3-pyridinylcarbonyl) carbamic acid 19,20-dihydro-2- (S) -hydroxymutillin 14-ester;
(6-dimethylamino-3-pyridinylcarbonyl) carbamic acid 2- (S) -hydroxymutinine 14-ester; And
A compound of formula I selected from the group consisting of (3-amino-6-pyridazinylcarbonyl) carbamic acid 2- (S) -hydroxymutiline 14-ester.
[8" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier or excipient.
[9" claim-type="Currently amended] The compound of claim 1 for treatment.
[10" claim-type="Currently amended] Reacting a compound of formula II with an acyl isocyanate of formula R ^1A CONCO, wherein R ^1A is R ¹ as defined above or a group convertible to R ¹ , eg, a group comprising a protected substituent, As required,
(i) deprotecting the P and / or X groups to generate hydroxyl groups at the 2 or 11 position, respectively,
(j) converting the R ^1A group to R ¹ , eg removing a protecting group,
(k) converting the R ¹ group to another R ¹ group, and
(l) hydrogenating the vinyl group at position 12 to form an ethyl group
Method for producing a compound of formula (I) comprising a.
<Formula II>

Wherein X and P are hydrogen or a hydroxyl protecting group such as an acyl group, and R ² is as defined in claim 1.
[11" claim-type="Currently amended] A compound of formula II
<Formula II>

Wherein P and X are hydroxyl protecting groups and R ² is as defined in claim 1.

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US6972297B2|2005-12-06|

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WO2001074788A1|2001-10-11|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-04-04|Priority to GBGB0008260.2A

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2000-04-04|Priority to GB0008260.2

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2000-11-04|Priority to GB0027182.5

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2000-11-04|Priority to GB0027182A

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2001-03-29|Application filed by 스미스클라인비이참피이엘시이

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2001-03-29|Priority to PCT/EP2001/003594

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2003-02-11|Publication of KR20030011815A

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2007-09-14|Application granted

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2007-09-14|Publication of KR100758441B1

优先权:

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申请号 | 申请日 | 专利标题

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GBGB0008260.2A|GB0008260D0|2000-04-04|2000-04-04|Novel compounds|

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GB0008260.2|2000-04-04|

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GB0027182.5|2000-11-04|

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GB0027182A|GB0027182D0|2000-11-04|2000-11-04|Novel comounds|

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PCT/EP2001/003594|WO2001074788A1|2000-04-04|2001-03-29|2-hydroxy-mutilin carbamate derivatives for antibacterial use|