LV11525B - Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone - Google Patents

Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone Download PDF

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LV11525B
LV11525B LVP-96-151A LV960151A LV11525B LV 11525 B LV11525 B LV 11525B LV 960151 A LV960151 A LV 960151A LV 11525 B LV11525 B LV 11525B
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alkyl
aryl
hydrogen
optionally substituted
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Gregori J Morriello
Arthur A Patchett
Yang Lihu
Meng H Chen
Nargund Ravi
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Merck & Co Inc
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Priority claimed from US08/323,998 external-priority patent/US5492920A/en
Priority claimed from US08/323,994 external-priority patent/US5494919A/en
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of LV11525A publication Critical patent/LV11525A/en
Publication of LV11525B publication Critical patent/LV11525B/en

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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description

- 1 - LV 11525
TITLE OF THE INVENTION
PIPERIDINES, PYRROLIDINES AND ΗΕΧ AHYDRO-1H-AZEPINES PROMOTE RELEASE OF GROWTH HORMONE
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of copending application Senai No. 08/323,994, filed October 17,1994, which is a continuation-in-part of copending application Senai No. 08/149,441, filed November 9,1993; a continuation-in-part of copending application Senai No. 08/323,998, filed October 17,1994, which is a continuation-in-part of copending application Senai No. 08/165,149, filed December 10, 1993; and a continuation-in-part of copending application Serial No. 08/323,988, filed October 17,1994, which is a continuation-in-part of copending application Serial No. 08/173,449, filed December 23, 1993.
BACKGROUND OF THE INVENTION
Growth hormone, which is secreted from the pituitary, stimulates growth of ali tissues of the body that are capable of grovving.
In addition, growth hormone is known to have the follovving basie effects on the metabolic processes of the body: (1) Increased rāte of protein synthesis in ali celis of the body; (2) Decreased rāte of carbohydrate utilization in celis of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy. A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are knovvn to release growth hormone. For example, Chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as vvell as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to inerease the secretion of the knovvn secretagogue grovvth hormone releasing factor (GRF) or an unknovvn endogenous grovvth hormone-releasing hormone or ali of these. -Ί λη cases where increased Ievels of growth hormone vvere desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and ciarried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the grovvth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is stili a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Patent 4,411,890. These peptides, while considerably smaller than growth hormones are stili susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. Non peptidal growth hormone secretagogues with a benzolactam structure are disclosed in U.S. Patents 5,206,235, 5,283,241,5,284,841, 5,310,737 and 5,317,017. The instant compounds are low molecular weight peptide analogs for promoting the release of growth hormone which have good stability in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.
SUMM ARY OF THE INVENTION
The instant invention is directed to certain piperidine. pvrrolidine, and hexahydro-lH-azepine compounds which have the ability to stimulate the release of natūrai or endogenous growth hormone. The compounds thus have the ability to be used to treat conditions vvhich require the stimulation of growth hormone production or secretion such as in humāns with a deficiency of natūrai growth hormone or in animals used for food production vvhere the -3- LV 11525 stimulation of growth hormone will result in a larger, more productive animal. Thus, it is an object of the instant invention to describe the piperidine, pyrrolidine, and hexahydro-lH-azepine compounds. It is a further object of this invention to describe procedures for the preparation of such compounds. A stili further object is to describe the use of such compounds to increase the secretion of growth hormone in humāns and animals. A stili further object of this invention is to describe compositions containing the piperidine, pyrrolidine, and hexahydro-lH-azepine compounds for the use of treating humāns and animals so as to increase the Ievel of growth hormone secretions. Further objects will become apparent from a reading of the following description.
DESCRIPTION OF THE INVENTION
The novel piperidine, pyrrolidine, and hexahydro-lH-azepine compounds of the instant invention are best described in the follovving structural formula I: Η Η O r. I. I II .4 —N-C-A-N C=0 Rs (CH^y-w 25 wherein:
R3 γ Formula I Rļ is selected from the group consisting of: Cļ-CiO alkvl, arvl, aryl(Cļ-C6 alkyl), (C3-C7 cycloalkyl)(Ci-C6 alkvl)-. 3C (C1-C5 alkyl)-K-(Cl-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Ci-C5 alkvl)-. and (C3-C7 cycloalkyl)(C0-C5 alkyl)-K-(C]-C5 alkyl)-, where K is O. S(0)m, N(R2)C(0), C(0)N(R2), OCfO), C(0)0, -CR2=CR2-. or -OC-. where arvl is selected from: phenyl, naphthyl, indolvl, azaindole. pyridyl, benzothienyl. benzofuranyl, thiazolyl, and benzimidazolvl. and R2 and alkvl may be further substituted by 1 to 9 halogen, S(0)mR2a< 1 -4- to 3 of OR2a or C(0)0R2ai and aryl may be further substituted by 1 to 3 of Cļ-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0)mR2, 1 to 2 of-CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -lH*tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyĻ or -N(R2)S02R2; R2 is selected from: hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl, and vvhere two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-Cg cyclic ring, optionaily including oxygen, sulfur or NR3a; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; R3 is selected from: hydrogen, -(CH2)rphenyl, -(CH2)rnaphthyl, -C1-C10 alkyl, -C3-C7 cycloalkyl, where the phenyl, naphthyl and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR2, -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6). -(CH2)r (Re). -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)r0C(0)R6, -fCH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2). -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6,-(CH2)rN(R2)C(0)NCR2)CR6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2. CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)r0C(0)N(R2)(R2),-(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2).(CH2)rS02NHC(0)R6, -rCH2)rS02NHC(0)R2. -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -fCH2)rC(0)NHC(0)R2, -(CH2)rCONHCfO)R6, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, -(CH2)rC0NHS02N(R2)R2), -(CH2)rC0NHS02N(R2)R6), -5- LV 11525 -(CH2)rN(R2)S02N(R2)R6), -(CH2)rN(R6)S02N(R2)R6), -(CH2)rS(0)mR6> and -(CH2)rS(0)niR2; R3a is hydrogen, or C\-Ce alkyl optionally substituted by hydroxyl; W is selected from the group consisting of: hydrogen, -CN, -C(0)0R8, -C(0)0R2, -C(0)0(CH2)laryl, -C(0)N(R2)(R2): -C(0)N(R2)(R8). -C(0)N(R2)(CH2)1 aryl, -CH2N(R2)C(0)R8 -CH2N(R2)C(0)(CH2)iaryl, -(CH2)rOR2, -CH(OH)R2, -CH(OH)(CH2)laryl, -C(0)R2, -C(0)(CH2)l aryl, lH-tetrazol-5-yl, 5-amino-l, 2,4-oxadiazol-3-yl, and 5-methyl-l, 2,4-oxadiazol-3-yl, where R8 is hydrogen, Cl-C6 alkyl, or Ci-C6 alkyl substituted by OR2, C(0)0R2, CON(R2)(R2), N(R2)C(0)R2, N(R2)C(0)N(R2)(R2). and aryl is phenyl, pyridyl, or lH-tetrazol-5- yi; X is selected from the group consisting of: hydrogen, -C=N, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S02(CH2)tarylt-(CH2)qN(R2)S02R2. -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taiyl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)q0C(0)N(R2)(CH2)taryl, -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2, and -CCH2)qS(0)mfCH2)taryl, where an R2. (CH2)q and (CH2)t group may be optionally substituted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy. carboxyl, CONH2, SfO)mCH3, carboxylate C1-C4 alkvl esters, or lH-tetrazol-5-yl. and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which mav be optionallv substituted by 1 to 3 halogen, 1 to 3 -OR2. -CON(R2)(R2h -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; -6- Υ is selected from the group consisting of: hydrogen, Cl-CiO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Ci-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, C^C, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; vvith the proviso that at least one of R3, W, X, and Y are other than hvdrogen; R4 and R5 are independently hydrogen, C1-C6 alkyl, substituted Cl-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-ClO alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, C1-C6 a!koxycarbonyl, S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)dLa(CH2)e- where La is C(R2)2, 0, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defined above; A is:
or
where x and y are independently 0, 1. 2 or 3; Z is N-R6a or O, where R6a is hvdrogen or C1-C6 alkyl; -7- LV 11525 R6 is hydrogen, Cl-C6 alkyl, or (CH2)varyl, wherein the alkyl and (CH2)v groups may be optionally substituted by 1-2 0(R2), S(0)mR2. lH-tetrazol-5-yl, C(0)0R2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2),and wherein aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-l-yl, benzimidazol-2-yl, triazolinone-yl optionally substituted with C]-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; R7 and R7a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0(Ci-C6 alkyl), C3-C7 cycloalkyl, N(R2)(R2). C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms; or R7 and R7a can be joined to one another to form a C3-C7 cycloalkyl; 1 is 0, 1 or 2; m is 0, 1, or2; n is 1,2, or3; q is 0,1, 2,3, or4; ris 0,1,2, or 3; tis 0,1,2, or3; v is 0, 1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof.
When n is 1, a pynolidine ring is formed, when n is 2 a piperidine ring is formed and when n is 3 the ring is designated as a hexahydro-1 H-azepine.
In the above structural formula and throushout the instant w specification, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration which may optionally contain double or triple -8- bonds. Exemplary of such alkyl groups are methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), sec-butyl (s-Bu), tertiary butyl (t-Bu), pentyl, isopentyl, hexyl, isohexyl, allyl, propinyl, butadienyl, hexenyl and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, teniary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propinyloxy, isobutenyloxy, hexenyloxy and the like.
The term "halogen" is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
The term "aryl" within the present invention, unless othenvise specified, is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected the group consisting of: phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazoiyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl, which may be optionally substituted by 1 to 3 of Ci-C6 alkyl, 1 to 3 of halogen, 1 to 2 of -OR.2, methylenedioxy, -S(0)mR~, 1 to 2 of -CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(r2), -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl, or -N(R2)S02R2, wherein R2 is as defined herein.
Certain of the above defmed terms may occur more than once in the above formula or definitions and upon such occurrence, each term shall be defined independently of the other. -9- LV 11525 A first embodiment of the present invention is directed to the compounds of the structural formula AI: Η Η O R, r i u / 4 Rļ—ļ-"N“C~A—N C=0 Rs (CH2^yw M-x R3 γ
Formula AI wherein:
Rl is selected from the group consisting of:
Cl-Cio alkyl, aryl, aryl(Ci-C6 alkyl), (C3-C7 cycloalkyl)(Ci-C6 alkyl)-, (C1-C5 alkyl)-K-(Cļ-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Cl-C5 alkyl)-, and (C3-C7 cycloalkyl)(C0-C5 alkyl)-K-(Ci-C5 alkyl)-, where K is 0, S(0)m, N(R2)C(0), C(0)N(R2), OC(O), C(0)0, -CR2=CR2-, or-OC-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a, 1 to 3 of OR2a or C(0)0R2a> and aryl may be further substituted by 1 to 3 of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0)mR2, 1 to 2 of-CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2)> -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl. or -N(R2)S02R2; R2 is selected from: hvdrogen, C1-C6 alkyl, and C3-C7 cycloalkyl, and vvhere two CJ-C6 alkyl groups are present on one atom. they mav be optionally joined to form a C3-C8 cvclic ring, optionally including oxygen, sulfur or NR3a; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; R3 is selected from: hydrogen, -fCH2)rphenyl, -(CH2)rnaphthyl. -C1-C10 alkvl, -C3-C7 cvcloalkvl, where the phenyl, naphthvl and C3-C7 cvcloalkvl rings mav be substituted by 1 to 3 substituents selected from - 10- the group consisting of: Cļ-C6 alkyl, halogen, -OR2, -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r (Re), -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6). -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6,-(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)SC>2R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rSC>2NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2 , -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, .(CH2)rC0NHS02N(R2)R2), -(CH2)rC0NHS02N(R2)R6), -(CH2)rN(R2)S02N(R2)R6),-(CH2)rN(R6)S02N(R2)R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; W is selected from the group consisting of: -CN, -C(0)0R8, -C(0)0R2, -C(0)0(CH2)iaryl, -C(0)N(R2)(R2); -C(0)N(R2)(R8), -C(0)N(R2)(CH2)1 aryl, -CH2N(R2)C(0)R8 -CH2N(R2)C(0)(CH2)iaryl, -(CH2)rOR2, -CH(OH)R2, -CH(OH)(CH2)iaryl, -C(0)R2, -C(0)(CH2)l aryl, lH-tetrazol-5-yl, 5-amino-l, 2, 4-oxadiazol-3-yl. and 5-methyl-l, 2, 4-oxadiazol-3-yl, where R8 is hydrogen, C1-C6 alkyl, or C1-C6 alkyl substituted by OR2, C(0)0R2, CON(R2)(R2). N(R2)C(0)R2, N(R2)C(0)N(R2)(R2), and aryl is phenyl, pyridyl, or lH-tetrazol-5- yi; - 11 - LV 11525 X is selected from: hydrogen, -CsN, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl,-(CH2)qN(R2)S02(CH2)taryl, -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taiyl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)q0C(0)N(R2)(CH2)taryl, -(CH2)qOC(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2. and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substituted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2)> -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from: hvdrogen, Cl-CiO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing 0, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, OC, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl. naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substimted bv 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; R4 and R5 are independently hvdrogen, C1-C6 alkyl. substituted Cl-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-ClO alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy. 2- - 12- furyl, Cl-C6 alkoxycarbonyl, S(0)m(Cl-Q> alkyl); or R4 and R5 can be taken together to form -(CH2)dLa(CH2)e- where La is C(R2)2> O, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defined above; A is: or — (CH2)x-C-(CH2)y- R7a -Z-(CH2)x-C-(CH2)y- R7a where x and y are independently 0, 1, 2 or 3; Z is N-R6a or 0, where R6a is hydrogen or C1-C6 alkyl; R6 is hydrogen, C1-C6 alkyl, or (CH2)varyl, wherein the alkyl and (CH2)v groups may be optionally substituted by 1-2 0(R2)> S(0)mR2> lH-tetrazol-5-yl, C(0)OR2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2)»and wherein aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-l-yl, benzimidazol-2-yl, triazolinone-yl optionally substituted with Cl-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; R7 and R7a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0(Cl-C6 alkyl). C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the termiņai nitrogen and the alkyl ponion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms: or R7 and R7a can be joined to one another to form a C3-C7 cvcloalkvl: 1 is 0, 1 or 2; m is 0, 1. or 2; -13- LV 11525 n is 1, 2, or 3; q is 0, 1, 2, 3, or4; r is 0, 1, 2, or 3; t is 0, 1,2, or 3; v is 0, 1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof. 10
Preferred compounds within this first embodiment include those of Formula Ala: Η Η O R. R1 N-C-A-N C=0 R5 <ch2i!Vw r3 y
Formula Ala wherein: R i is selected from the group consisting of:
Ci-CiO alkyl, aryl (C1-C4 alkyl)-, C3-C6 cycloalkyl (C1-C4 alkyl)-, (C1-C4 alkyl)-K-(Cl-C2 alkyl)-, aryl (C0-C2 alkyl)-K-(Cļ-C2 alkyl)-, and (C3-C7 cycloalkyl)(Co-C2 alkyl)-K-(Cļ-C2 alkyl)-, where K is O, S(0)m, OC(O), C(0)0 and the alkyl groups may be further substituted by 1 to 7 halogen, S(0)mR2, 1 to 3 OR2 or C(0)OR2 and aryl is phenyl, naphthvl, indolyl, pyridyl, benzothienyl, or benzofuranyl which may be further substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)mR2 or C(0)OR2; R2 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C4-C7 cyclic ring optionally including oxygen, sulfur or NR3a; - 14- R3 is hydrogen or phenyl optionally substituted in the ortho position by a C1-C6 alkyl group, -NHSO2CF3, -(CH2)r (lH-tetrazol-5-yl), -(CH2)rC(0)0R2, (CH2)rC(0)N(R2)(R6); 5 R3a is hydrogen, or C1-C4 alkyl; W is -CN, -C(0)0R2, -C(0)N(R2)(R2), -C(0)N(R2)(CH2)l phenyl, lH-tetrazol-5-yl, or -(CH2)rOR2; 10 X is hydrogen, -(CH2)qC(0)N(R2)(R6). or -(CH2)qC(0)0R2; Y is hydrogen, C1-C8 alkyl, -(CH2)t phenyl, -(CH2)t pyridyl, or -(CH2)tthiazolyl; 15 R4 and R5 are independently hydrogen, C1-C6 alkyl, or substituted Ci-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(0)m (C ļ-C6 alkyl) or phenyl; R6 is hydrogen, or C1-C6 alkyl; 20 A is: (CH2)x-C— 25 ^7a where x is 0, or 1; R7 and R7a are independently hydrogen C1-C6 alkyl, trifluoromethyl, phenyl, substituted Cļ-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0(Cļ-C6 alkyl), C5-C7 cycloalkyl, N(R2)(R2). C(0)N(R2)(R2); or R7 and R7a can independently be joined to one of R4 or R5 to form alkylene bridges between the termiņai nitrogen and the alkyl portion of R7 or R7a groups to form 5 or 6 membered rings; or R7 and R7a can be joined to one another to form a C3 cycloalkyl; - 15- LV 11525 1 is 0 or 1; n is 2; m is 0,1, or 2; r is 0, 1,2 or 3; q is 0 or 1 t is 0 or 1; and pharmaceutically acceptable salts and individual diastereomers thereof.
More preferred compounds vvithin this first embodiment include those of Formula Alb: Η Η O r, = I II »4 Rļ—p"N-C-A-Ņ C=0 R5
R3
Formula Alb wherein: Rļ is selected from the group consisting of: Cl-ClO alkyl, aryl (C1-C3 alkyl)-, and aryl (C0-C1 alkyl)-K-(Ci-C2 alkyl)-, where K is O or S(0)m and the aryl is phenyl, pyridyl, naphthyl, or indolyl which are optionally substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)m R2 orC(0)OR2; R2 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cvclic ring optionally including oxygen, sulfur or NR3a; R3 is hydrogen or phenyl optionally substituted in the ortho position by a C1-C3 alkyl group, (CH2)r(lH-tetrazol-5-yl) or (CH2)rC(0)0R2; - 16- R3a is hydrogen, or C1-C4 alkyl; W is -CN, -C(0)0R2, or -C(0)N(R2)R2); X is hydrogen or C(0)0R2; Y is hydrogen, benzyl, picoyl, or thiazolylmethyl; R4 and R5 are independently hydrogen, C1-C3 alkyl, substituted C1-C3 alkyl where the substituents may be 1 to 2 hydroxyl; A is (CH2)x—C— ^7a where x is 0, or 1; R7 and R7a are independently hydrogen or C1-C4 alkyl; m is 0, 1, or 2; r is 0,1, or2; and pharmaceutically acceptable salts and individual diastereomers thereof.
The most preferred growth hormone releasing compounds vvithin this first embodiment include the following: - 17- LV 11525
nh2
I - 18-
-19- LV 11525
and pharmaceutically acceptable salts and individual diastereomers thereof. A second embodiment of the present invention is directed 15 to the compounds of the structural formula BI: R1
Η H 0 I II R t 4 --N-C-A-N C=0 r5 20
(CHiS
X
Y
Formula BI 25 wherein:
Rl is selected from the group consisting of:
Ci-Cio alkyl, aryl aryl(Ci-C6 alkyl), (C3-C7 cycloalkyl)(Ci-C6 alkyl)-, (C1-C5 alkyl)-K-(Ci-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Cl-C5 alkyl)-, and (C3-C7 cycloalkyl)(Co-C5 alkyl)-K-(Ci-C5 alkyl)-, where K is 0, 30 S(0)m. N(R2)C(0), C(0)N(R2), OC(O), C(0)0, -CR2=CR2-, or -CsC-. where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a> 1 to 3 of OR2a or C(0)0R2a» and aryl may be further substituted by 1 to of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -20- -S(0)mR2> 1 to 2 of -CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -lH-tetrazol-5-yl, -S02N(R2)(R2). -N(R2)SC>2 phenyl, or -N(R2)S02R2; R2 is selected from: hydrogen, Cļ-C6 alkyl, and C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring, optionally including oxygen, suLfur or NR3a, where R3a is hydrogen, or C1-C6 alkyl, optionally substituted by hydroxyl; R2a is hydrogen, or Cļ-C6 alkyl optionally substituted by hydroxyl; R3 is selected from: -(CH2)rphenyl, -(CH2)rnaphthyl, -C1-C10 alkyl, -C3-C7 cycloalkyl, and the phenyl, naphthyl and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR2, -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r (Rč), -(CH2)rC(0)OR2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)r0C(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, .(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rNfR2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6, .(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, .(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHCf0)R6, .(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2, -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2. .(CH2)rC0NHS02N(R2)R2), -(CH2)rC0NHS02N(R2)R6)> - (C H 2) rN (R2)S02N (R2)R6)»-(CH2)rN(R6)S02N(R2)R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; -21 - LV 11525 R3a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; X is selected from: hydrogen, -CsN, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S02(CH2)taryl, -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2). -(CH2)qC(0)N(R2)(CH2)taiyl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)q0C(0)N(R2)(CH2)taryl, -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substituted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2), -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from: hydrogen, Cl-ClO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing 0, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, C=C, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2,1 to 2 -N(R2)(R2),-C(0)0R2, -C(0)N(R2)(R2)> nitro, -NHC(0)R2,cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; -22- R.4 and R5 are independently hydrogen, C1-C6 alkyl, substituted Cļ-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-CļO alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, Cļ-C6 alkoxycarbonyl, S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)dLa(CH2)e- where La is C(R2)2> O, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defined above; A is: or — (CH2)„-C-(CH2)r ^7a Z-(CH2)x-C-(CH2)r ^7a where x and y are independently 0, 1, 2 or 3; Z is N-R6a or O, where R6a is hydrogen or Cļ-C6 alkyl; R6 is hydrogen, Cļ-C6 alkyl, or (CH2)varyl, wherein the alkyl and (CH2)v groups may be optionally substituted by 1-2 0(R2), S(0)mR2> lH-tetrazol-5-yl, C(0)0R2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2)»and wherein aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-l-yl, oxadiazolyl, benzimidazol-2-yl, triazolinone-yl, optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; R7 and R7a are independently hydrogen, C]-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR27 C(0)0R2, C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, vvherein the bridge contains 1 to 5 carbons atoms; or R7 and R7a can be joined to one another to form a C3-C7 cvdoalkyl: -23- LV 11525 m is 0, 1, or 2; n is 1, 2, or 3; q is 0, 1, 2, 3 or 4; r is 0, 1, 2, or 3; t is 0,1,2, or 3; v is 0,1, or2 ; and pharmaceutically acceptable salts and individual diastereomers thereof.
Preferred compounds within this second embodiment include those of Formula Bla:
Η Η O
Rr
I II
-N-C-A-N c=o
Formula Bla wherein: Rļ is selected from the group consisting of:
Ci-CiO alkyl, aryl (C1-C4 alkyl)-, C3-C6 cycloalkyl (C1-C4 alkyl)-, (C1-C4 alkyl)-K-(Ci-C2 alkyl)-, aryl (C0-C2 alkyl)-K-(Ci-C2 alkyl)-, and (C3-C7 cycloalkyl)(Co-C2 alkyl)-K-(Ci-C2 alkyl)-, where K is O, S(0)m. OC(0), or C(0)0, and the alkyl groups may be further substituted by 1 to 7 halogen, S(0)mR2> 1 to 3 OR2 or C(0)OR2, and aryl is phenyl, naphthyl, indolyl, pyridyl, benzimidazolyl, azaindolevl, benzothienyl or benzofuranyl which may be further substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 -OR2, -S(0)mR2, or -C(0)OR2; R2 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C4-C7 cyclic ring optionally including oxygen, sulfur or NR3a; -24- R.3 is phenyl which is optionally substituted by 1 to 2 Cļ-C6 alkyl groups, 1 to 2 halogen, or 1 to 2 -OR2, and which may be fiirther substituted in the ortho position by a substitutent selected from the group consisting of: -NHSO2CF3, -(CH2)rOR6, -(CH2)rN0*2)(R6). -(CH2)r 0*6). -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, .(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6, .(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, .(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6),-(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2, -(CH2)rCONHC(0)R6, -(CH2)rC0NHS02R6r(™2)rC0NHS02R2, .(CH2)rC0NHS02N(R2)R2),-(CH2)rC0NHS02N(R2)R6), -(CH2)rN(R2)S02N(R2)R6),-(CH2)rN(R6)S02N(R2)R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl,(-CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02(CH2)taryl. -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2). -(CH2)qC(0)N(R2)(CH2)taiyl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOC(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)qS(0)mR2, and -25- LV 11525 -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally substituted by hydroxyl, carboxyl, CONH2, S(0)mCH3, carboxylate Cļ-C4 alkyl esters, or tetrazole and the aryl which is phenyl, naphthyl, pyridyl or l-H-tetrazolyl may be optionally substituted by 1 to 2 halogen, 1 to 2 -OR2, -CONH2, -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or 1H-tetrazole-5-yl; Y is selected from: hydrogen, C1-C8 alkyl, (CH2)taryl, -(CH2)q(C5-C6 cycloalkyl), -(CH2)q-K-(Ci-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR2, or S), and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is O or S(0)m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and the aryl which is phenyl, naphthyl, pyridyl, 1-H-tetrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiopheneyl is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2,1 to 2 -N(R2)(R2), -C(0)0R2, -C(0)N(R2)(R2), cyano, 1 to 2 C1-C4 alkyl, benzyl, -S(0)mR2, or lH-tetrazol-5-yl; R4 and R5 are independently hydrogen, Cļ-C6 alkyl,or substituted Cļ-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(0)m (C1-C6 alkyl) or phenyl; R6 is H, C1-C6 alkyl, or (CH2)varyl, wherein the (CH2)v and alkyl groups may be optionally substituted by 1-2 0(R2), S(0)mR2> C(0)0R2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2), wherein the aryl group could be phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; A is: -26- (CH2)x—C — '7a 5 where x is 0, or 1; R7 and R7a are independently hydrogen Cļ-C6 alkyl, trifluoromethyl, phenyl, substituted Ci-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0R2, C5-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can 10 independently be joined to one of R4 or R5 to form alkylene bridges between the termiņai nitrogen and the alkyl portion of R7 or R7a groups to form 5 or 6 membered rings; or R7 and R7a can be joined to one another to form a C3 cycloalkyl; 15 n is 2; m is 0, 1, or 2; r is 0, 1, 2, or 3; q is 0, 1, 2, or 3; t is 0, 1, 2, or 3; 20 v is 0, 1, or 2, and pharmaceutically acceptable salts and individual diastereomers thereof. 30 -27- LV 11525
More preferred compounds within this second embodiment include those of Formula BIb:
Ri—c-n-c-a-n:
Formula BIb wherein:
Rl is selected from the group consisting of: Cl-ClO alkyl, aryl (C1-C3 alkyl)-, (C3-C7 cycloalkyl)(Cl-C3 alkyl)-, and aryl (Cq-C\ alkyl)-K-(Cļ-C2 alkyl)-, where K is O or S(0)m and aryl is specifically phenyl, pyridyl, naphthyl, indolyl, azaindolyl, or benzimidazolyl which is optionally substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)m R2, or C(0)0R2; R2 is hydrogen, Cļ-C6 alkyl, C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3 is phenyl optionally substituted by 1 to 2 C1-C6 alkyl groups, 1 to 2 halogen or 1 to 2 OR2, and which may be further substituted in the ortho position by a substitutent selected from the group consisting of: -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6). -(CH2)r (R6), -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)iC(0)N(R2)(R2), -(CH2)iC(0)N(R2)(R6). -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6,-(CH2)rN(R2)C(0)N(R2)(R6)> -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), -28- (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or Cl-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)q N(R2)S02(CH2)taryl, -(CH2)q N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qN(R2)C(0)0R2, -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally substituted by hydroxyl, carboxyl, -CONH2, -S(0)mCH3, carboxylate C1-C4 alkyl esters or tetrazole and aryl is phenyl, napthyl or pyridyl which may be further substituted by 1-2 halogen, 1 to 2 OR2, C(0)0R2, 1 to 3 C1-C4 alkyl, S(0)mR2> or lH-tetrazole-5-yl; Y is selected from: hydrogen, Cļ-C8 alkyl, (CH2)taryl, -(CH2)q C5-C7 cycloalkyl, -(CH2)q-K-(Cļ-C6 alkyl), -(CH2)q-K-(CH2)taryl, and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is S(0)m and vvhere the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and aryl is specifīcally phenyl, napthyl, pyridyl, thiazolyl,.thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 OR2, 1 to 2 -N(R2)(R2), -CO(OR2), 1 to 2 Cļ-C4 alkyl, S(0)mR2> or lH-tetrazol-5-yl; -29- LV 11525 R4 and R5 are independently hydrogen, C1-C4 alkyl, substituted C1-C3 alkyl where the substituents may be 1 to 2 hydroxyl; R6 is hydrogen, C1-C6 alkyl or (CH2)varyl, wherein the C1-C6 alkyl and the (CH2)Varyl groups may be optionally substituted by 1-2 0(R2), S(0)mR2, C(0)0R2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2), wherein aryl is specifically phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with Cl-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; A is '7a (CH2)x-C — R, where x is 0, or 1; R7 and R7a are independently hydrogen, Cļ-C2 alkyl, phenyl, substituted Cļ-C6 alkyl wherein the substitutent is imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2; or R7 and R7a can be independently be joined to one another to form a C3 cycloalkyl; m is 0, 1, or 2; r is 0, 1, 2, or 3; q is 0, 1, 2, or 3; t is 0, 1,2, or3; v is 0, 1, or 2; and pharmaceutically acceptable salts and individual diastereomers thereof.
Stili more prefenred compounds within this second embodiment are realized in Formula BIc: -30- -30- r4 r5 b Η
Ri—c-n-c-a-n:
I II c=o o
X R3
Formula BIc wherein: Rļ is selected from the group consisting of:
(1-2)F rv ,CH;
N' H
H CH2-
0-2)
or their regioisomers where not specified; -31 - LV 11525 R2 is hydrogen, Cļ-C6 alkyl, or C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3 is phenyl optionally substituted in the ortho position with a substitutent selected from the group consisting of: -NHSO2CF3, -(CH2)rOR6, -(CH2)r (R6). -(CH2)rC(0)OR2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)r0C(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6, -(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, -(CH2)r0C(0)N(R2)(R6), -(CH2)r0C(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C4 alkyl; X is selected from the group consisting of: hydrogen, -32- ο ο ο ο ch3 Α,λη, Λ0-ε' Λ0^ ^oAch3 ο
A'ch= Η Ν' Η
ΟΗ Ο CH3CH* AnAch Η 3
Υ is selected from the group consisting of: hydrogen, Cļ-C8 alkyl, (CH2)taryl, -(CH2)q C5-C7 cycloalkyl, -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, or -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl) where K is S(0)m and where the alkyl groups may be -33- LV 11525 optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate Cļ-C4 alkyl esters or lH-tetrazole-5-yl, and where aryl is specifically phenyl, naphthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrimidinyl, or imidazolyl, which may be optionally substituted by 1 to 2 halogen, 1 to 2 OR2, CO(OR2), 1 to 2 C1-C4 alkyl, S(0)mR2 or lH-tetrazol-5-yl; A is selected from the group consisting of:
ch3 h3c ch3y VV W ^'V
HaC\ >CH3 H3Cx.CH3 CH3 CH, H,C, .CH,
R4 and R5 are independently selected from the group consisting of: —H — CH3 — CH2CH3 ^^γ0Η 3 /-γ0Η20Η
OH OH R6 is hydrogen, C1-C6 alkyl or (CH2)varyl wherein the alkyl and (CH2)v groups may be optionally substituted by halogen, OR2, N(R2)(R2), C3-C6 cycloalkyl, lH-tetrazol-5-yl, C(0)0R2, C(0)N(R2)(R2), S02N(R2)(R2) or N(R2)C(0)N(R2)(R2), wherein aryl is selected from the following aromatic groups and their regioisomers: >0 -34-
Η Ν ν-ν Η
oi/ S—Ν
Ο-Ν
0-Ν , where the aromatic groups are optionally substituted with C1-C2 alkyl, -N(R2)(R2), or hydroxy; m is 0, 1, or 2; r is 0, 1,2, or 3; q is 0 or 1; t is 0 or 1; v is 0 or 1; and pharmaceutically acceptable salts and individual diastereomers thereof.
Representative of the stili more preferred compounds vvithin this second embodiment include the following: -35-LV 11525
-36-
ΝΗ2
cis dļ. cis d2. trans d·,. trans d2
cis dļ. cis d2. trans dv trans d2 -37- LV 11525
and pharmaceutically acceptable salts and individual diastereomers thereof where not othenvise specified.
Ali of the stili more preferred compounds shown above have 15 at least one asymmetric center. Additional asymmetric centers may be present on the molecule depending upon the nature of the substituents on the piperidine ring. Each such asymmetric center will producē two optical isomers and it is intended that ali such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or 20 diastereomeric mixtures thereof, be included within the ambit of the present invention.
The most preferred compounds within this second embodiment include the follovving:
-38-
» -39- LV 11525
cis dļ. cis d2
and their pharmaceutically acceptable salts and individual diasteromers thereof vvhere not otherwise specified. -40- A third embodiment of the present invention is directed to the compounds of the structural formula CI:
Η Η O I II I II /
Ri—— N-C-A-N C=0 Xi
Y
Formula CI wherein: Rļ is selected from the group consisting of:
Ci-Cio alkyl, aryl, aryl(Ci-C6 alkyl), (C3-C7 cycloalkyl)(Ci-C6 alkyl)-, (C1-C5 alkyl)-K-(Cļ-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Ci-C5 alkyl)-, and (C3-C7 cycloalkyl)(C0-C5 alkyl)-K-(Cl-C5 alkyl)-, where K is O, S(0)m, N(R2)C(0), C(0)N(R2), OC(O), C(0)0, -CR2=CR2-, or -C^C-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a, 1 to 3 of OR2a or C(0)0R2a, anc^ *0^ may be further substituted by 1 to 3 of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0)mR2, 1 to 2 of-CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)OR2, -C(0)N(R2)(R2). -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl, or -N(R2)S02R2; R2 is selected from: hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl, and where two Cļ-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR3a, where R3a is hydrogen, or C1-C6 alkyl, optionally substituted by hydroxyl; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; -41 - LV 11525 X is selected from: hydrogen, -G=N, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl,-(CH2)qN(R2)S02(CH2)taiyl, -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2),-(CH2)qC(0)N(R2)(R2), 5 -(CH2)qC(0)N(R2)(CH2)taryl,-(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taiyl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)qOC(0)N(R2)(CH2)taryl, -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), 10 -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substimted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be 15 optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2), -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from: hydrogen, Cļ-ClO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), 20 -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, Cs=C, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and vvhere the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, 2 5 carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), nitro, cyano, -an benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; R4 and R5 are independently hydrogen, Cļ-C6 alkyl, or substituted Ci-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 -42-
Cl-ClO alkanoyloxy, 1 to 3 Ci-C6 alkoxy, phenyl, phenyloxy, 2-furyl, Cl'Ce alkoxycarbonyl, S(0)m(Cl-C6 alkyl), or R4 and R5 may be taken together to form -(CH2)d-La(CH2)e- where La is -C(R2)2-, 0, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defined above; A is: — (CH2)x-C - (CHaJj- or — Z~ (CH2)X-C - (CH2)y— R7a R7a where x and y are independently 0,1, 2 or 3; Z is N-R6a or O, where R6a is hydrogen or C1-C6 alkyl; R7 and R7a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, or substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2> C(0)OR2, C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2), or Rj and R7a may independently be joined to one or both of R4 and R5 groups to form an alkylene bridge between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms, or R7 and R7a can joined to one another to form C3-C7 cycloalkyl; m is 0, 1, or 2; n is 1, 2, or 3; q is 0, 1, 2, 3, or 4; t is 0, 1,2, or 3; and pharmaceutically acceptable salts and individual diastereomers thereof. -43- LV 11525
Preferred compounds within this third embodiment include those of Formula CIa: H H p
l I /R R^C'-N-C-A-N I 11 v c=o 0 Rj (CH2)n^
Y
Formula CIa wherein: Rļ is selected from the group consisting of:
Ci-Cio alkyl, aryl (C1-C4 alkyl)-, C3-C6 cycloalkyl (C1-C4 alkyl)-, (C1-C4 alkyl)-K-(Cl-C2 alkyl)-, aryl (C0-C2 alkyl)-K-(Cl-C2 alkyl)-, and (C3-C7 cycloalkyl)(C0-C2 alkyl)-K-(Cl-C2 alkyl)-, where K is O, S(0)m> OC(O), or C(0)0, and the alkyl groups may be further substituted by 1 to 7 halogen, S(0)mR2, 1 to 3 OR2 or C(0)0R2, and aryl is phenyl, naphthyl, indolyl, pyridyl, benzimidazolyl, azaindoleyl, benzothienyl or benzofuranyl which may be further substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 -OR2, -S(0)mR2, or -C(0)0R2; R2 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C4-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02(CH2)taryl, -(CH2)qN(R2)SC>2R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)q0C(0)R2, -44- -(CH2)q0C(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally substituted by hydroxyl, carboxyl, CONH2, S(0)mCH3, carboxylate Ci-C4 alkyl esters, or tetrazole, and aryl is phenyl, naphthyl, pyridyl or 1-H-tetrazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 -OR2, -CONH2, -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or 1H-tetrazole-5-yl; Y is selected from: hydrogen, C1-C8 alkyl, (CH2)taryl, -(CH2)q(C5-C6 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloa!kyl containing O, NR2, or S), and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is O or S(0)m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazolyl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, or thiopheneyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), cyano, 1 to 2 C1-C4 alkyl, benzyl, -S(0)mR2, or lH-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; R4 and R5 are independently hydrogen, C1-C6 alkyl, or substituted Cl-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(0)m (C1-C6 alkyl) or phenyl; A is: (CH2)x—C— ^7a where x is 0, or 1; R7 and R7a are independently hydrogen Cļ-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl vvhere the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0R2, C5-C7 -45- LV 11525 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2); or R7 and R7a can independently be joined to one of R4 or R5 to form alkylene bridges between the termiņai nitrogen and the alkyl portion of R7 or R7a groups to form 5 or 6 membered rings; or R7 and R7a can be joined to one another to form a C3 cycloalkyl; n is 2; misO, l,or2; q is 0,1, 2, or 3; t is 0, 1, 2, or 3; and pharmaceutically acceptable salts and individual diastereomers thereof.
More preferred compounds within this third embodiment include those of Formula CIb:
Formula CIb wherein:
Rl is selected from the group consisting of: Cļ-ClO alkyl, aryl (C1-C3 alkyl)-, (C3-C7 cycloalkyl)(Ci-C3 alkyl)-, and aryl (Co-Cļ alkyl)-K-(Cļ-C2 alkyl)-, where K is O or S(0)m and the aryl is phenyl, pyridyl, naphthyl, indolyl, azaindolyl, or benzimidazolyl which is optionally substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)m R2, or C(Q)OR2; -46- R2 is hydrogen, Cl-C6 alkyl, or C3-C7 cycloalkyl, and where two Cļ-C6 alkyl groups are present on one atom they may be optionally joined to fonu a C5-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)q N(R2)S02(CH2)taiyl, -(CH2)q N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qN(R2)C(0)0R2, -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)q0C(0)R2, -(CH2)qOC(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryk where an R2 group may be optionally substituted by hydroxyl, carboxyl, -CONH2, -S(0)mCH3, carboxylate C1-C4 alkyl esters or tetrazole and aryl is phenyl, naphthyl or pyridyl which may be further substituted by 1-2 halogen, 1 to 2 OR2, C(0)0R2, 1 to 3 C1-C4 alkyl, S(0)mR2> or lH-tetrazole-5-yl; Y is selected from: hydrogen, Cļ-C8 alkyl, (CH2)taryl, -(CH2)q C5-C7 cycloalkyl, -(CH2)q-K-(Cļ-C6 alkyl), -(CH2)q-K-(CH2)taryl, and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is S(0)m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and aryl is phenyl, napthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 OR2, 1 to 2 -N(R2)(R2), CO(OR2), 1 to 2 C1-C4 alkyl, S(0)mR2> or lH-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; R4 and R5 are independently hydrogen, C1-C4 alkyl, or substituted Cļ-C3 alkyl where the substituents may be 1 to 2 hydroxyl; A is -47- LV 11525 (CH2)x—C— 7a
R where x is 0, or 1; R7 and R7a are independently hydrogen, Ci-C6 alkyl, phenyl, substituted Ci-C6 alky wherein the substitutent is imidixolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, or R7 and R7a may be joined to one another to form a C3 cycloalkyl; m is 0, 1, or 2; q is 0,1,2, or 3; t is 0,1, 2, or 3; and pharmaceutically acceptable salts and individual diastereomers thereof.
Stili more preferred compounds within this third embodiment include those of Formula CIc: H 1
H R1—C—N-C-A-N^ _ c=o 0
I
X Y
Formula CIc wherein:
Rl is selected from the group consisting of: 5 -48- 10 15 20
Ν' Η
ch2- ch3 ,CH;
(1-2)F-CC ,CHo- Ν' Η
^ch2-
H ch2- CH2-
ch2-
.CHo-
ch2-
(1-2) F-
d-2) F-^
CHo-
d-2)
ch2- 25 or their regioisomers where not specified; X is selected from the group consisting of: hydrogen, 30 LV 11525
Y is selected from the group consisting of: hydrogen, -50- H3C\^CH2.
HoC CH3
Et02C -ļf CH2-tetrazole-ļļ-CHr ^ 1-3 halogen-ļļ-CH2- ^ CH2-
ch2-
N
CH3 ch2- ^Tch2-
</ J-ch2-
N H
Η30-^ jļ CH2 H
</ jrCH2-H CH< or their regioisomers whereof where not specified, with the proviso that if X is hydrogen, Y is other than hydrogen; A is selected from the group consisting of: -51 - LV 11525
^CH3 h3c^ch3 3"3^ ^n3 ļ o ļ T h3cv ^ch3 HjC cHj 9h3
CH, H,C, ,CH' N<*\ W \
NH
vV W R4 and R5 are independently selected from the group consisting of:
—H —CH3 —CH2CH3 ^^γ0Η 3 /-rCH2OH
OH OH and pharmaceutically acceptable salts and individual diastereomers thereof.
The most preferred compounds within this third embodiment include the following:
-52-
NH(CH2)2SCH3 ο NHEt f 0
C=0 O
Η H
OEt
OEt r
0
-53- LV 11525
NHc
N' H
LJ U
C=0 0
NH2rr^^
„.0(CH2)2SMe (I
c 1γΝΗΕ» ^ N H ά fV V OEt
Y O
NHMe \^N \^N -54-
-55- LV 11525 "V^O'^f'N'C^NH2 J 9=0 0
and their pharmaceutically acceptable salts and individual diasteromers thereof where not othenvise specified.
Throughout the instant application, the following abbreviations are used with the following meanings: BOC t-butyloxycarbonyl BOP Benzotriazol-l-yloxy tris/dimethylamino)- phosphonium hexafluorophosphate CBZ Benzyloxycarbonyl -56- DIBAL-H diisobutylaluminum hydride DMF N,N-dimethylformamide EDC l-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride FAB-MS Fast atom bombardment-mass spectroscopy GHRP Growth hormone releasing peptide HOBT Hydroxybenztriazole LAH Lithium aluminum hydride HPLC High pressure liquid chromatography MHz Megahertz MPLC Medium pressure liquid chromatography NMM N-Methylmorpholine NMR Nuclear Magnetic Resonance TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Tetramethy lsilane
The compounds of the instant invention ali have at least one asymmetric center as noted by the asterisk in the structural Formula I above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will producē two optical isomers and it is intended that ali such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the ambit of the instant invention. In the case of the asymmetric center represented by the asterisk in Formula I, it has been found that the absolute stereochemistry of the more active and thus more preferred isomer is as shown in Formula II. An equivalent representation places Rl and the N-substituent in the planē of the structure with the C=0 group above. The special configuration of the asymmetric center corresponds to that in a D-amino acid. In most cases this is also -57- -57- LV 11525 designated an R-configuration although this will vary according to the value of Ri used in making R- or£- stereochemical assignments. Η Η O R. = i II ! '4
R1—ļ-N-C-A-N C=0 R5
I
W (CH2)ny r3 y
Formula II
The W group may also be present in either R- or S-configurations. Both afford active growth hormone secretagogues although, in general, the R- confīguration is more active. In addition, the W group may be cis- or trans- in respect to substituents X, Y or R3. In the case of the asymmetric center which bears the X and Y groups, in most cases, both the R- and S- confīgurations are consistent with useful Ievels of grovvth hormone secretagogue activity. In addition, confīgurations of many of the most preferred compounds of this invention are indicated. The W, X and Y groups may also be cis-or trans- to the R3 substituent. In some of the most preferred compounds a cis- or trans- relationship is also specified in respect to the R3 substitutent. Ali are vvithin the ambit of this invention and in some of the most preferred compounds these stereochemical orientations are indicated. When the carbon atom in Formula I bearing an asterisk is of a defined and usually a D-configuration, diastereomers result according to the absolute configuration at the carbon atoms bearing the W, X, Y and R3 groups. These diastereomers are arbitrarily referred to a diastereomers dl, d2, d3, d4, etc. and if desired, their independent syntheses or chromatographic separations may be achieved using Standard methods or as described herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates vvhich are derivatized, if necessary,. with a reaģent containing an asymmetric center of known absolute configuration. -58-
The instant compounds are g£nerally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
The preparation of compounds of Formula I of the present invention can be carried out in sequential or convergent synthetic routes. Syntheses detailing the preparation of the compounds of Formula I in a sequential manner are presented in the foliowing reaction schemes.
The phrase Standard peptide coupling reaction conditions is used repeatedly here, and it means coupling a carboxylic acid with an amine using an acid activating aģent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT. The uses of protective groups for amine and carboxylic acid to facilitate the desired reaction and minimizē the undesired reaction are well documented. Conditions required to remove protecting groups vvhich may be present and can be found in Greene, T; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991. CBZ and BOC were used extensively in the synthesis, and their removal conditions are known to those skilled in the art. Removal of CBZ groups can be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a nobel mētai or its oxide such as palladium on activated carbon in a protic solvent such as ethanol. In cases where catalytic hydrogenation is contraindicated by the presence of other potentially reactive functionality, removal of CBZ groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfīde. Removal of BOC protecting groups is carried out in a solvent such as methylene chloride or -59- LV 11525 methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
The protected amino acid derivatives 1 are, in many cases, commercially available, where the protecting group L is, for example, BOC or CBZ groups. Other protected amino acid derivatives 1 can be prepared by literature methods (Williams, R. M. Svnthesis of Opticallv Active α-Amino Acids. Pergamon Press: Oxford, 1989). Many of the piperidines, pyrrolidines and hexahydro-lH-azepines of formula 2 are either commercially available or known in the literature and others can be prepared following literature methods desribed for known compounds, some of which are described here. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those skilled in the art. Purification procedures includes crystallization, and normai phase or reverse phase chromatography. -60- SCHEME 1
Ri
Η H N-L
H H Rļ—ļ—N—L C02H (ch2)VWΜ-χ r3 y 1 2 C=0 N W (CH2)nVΜ-χ r3 _ γ
Intermediates of formula 3 may be synthesized as described in Scheme 1. Coupling of amine of formula 2 , whose preparations are described later if they are not known compounds, to protected amino acids of formula 1, wherein L is a suitable protecting group, is conveniently carried out under Standard peptide coupling conditions. SCHEME 2
R H H —N-L C=0 R1 (CH2iywHr* r3 y
Removal of L Η H --N-H C=0 (ch2)VWΜ-χ R3 y
Conversion of 3 to intermediate 4 can be carried out as illustrated in Scheme 2 by removal of the protecting group L (CBZ, BOC, etc.) using Standard methodology. -61 - LV 11525
SCHEME 3 H H R —(-N-H C=0 W -X
r3 y 7
Y
H (CH2)n > r3 4
Intermediates of formula 5, wherein A is connected to the carbonyl by a carbon atom and thus A is -(CH2)x-C(R7)(R7a)-(CH2)y- can be prepared as shown in Scheme 3 by coupling intermediates of formula 4 to amino acids of formula 5 under the Standard peptide coupling reaction conditions. The amino acids 5, as amino acid 1, are either commercially available or can be synthesized. Also if R4 or R5 is a hydrogen then the protected amino acids 6 are employed in the coupling reaction, vvherein L is a protecting group as defined above. The removal of L in 7 to afford I, vvhere R4 = H, can be carried out under conditions known in the art. -62- SCHEME4
Reductive alkylation or epoxide opening R4 A-N Rs Η Η Ο η | ι ιι Ρ
Rļ—|—N-C-A-N c=o r5
Η Η O
+ 1 II N-C- C=0
I where R4 is substituted /unsubstituted alkyl
Compounds of formula I wherein R4 and/or R5 is a hydrogen can be further elaborated to new compounds I (with most preferred side chains R4 = CH2-CH(OH)-CH2X, wherein X = H or OH) which are substituted on the amino group as depicted in Scheme 4. Reductive alkylation of I vvith an aldehyde is carried out under conditions known in the art; for example, by catalytic hydrogenation with hydrogen in the presence of platinum, palladium, or nickel catalysts or with Chemical reducing aģents such as sodium cyanoborohydride in a protic solvent such as methanol or ethanol in the present of catalytic amount of acid. Altematively, a similar transformation can be accomplished via an epoxide opening reaction. SCHEME 5 Η Η O R7 Z*a Rļ—ļ~N-H X-1" Z- (CH2)x-ļ- (CH2)yN ^ R?a R= c=o JSL W (CH2)ny R3 y
8 OR R,
Formula I 0= c= N- (CH2)x-ļ—(CH2)yN R- ^ ’7a R£ 9 -63- LV 11525
Compounds of formula I, wherein A is Z-(CH2)x-C(R7)(R7a)-(CH2)y and Z is N-R6 or O may be prepared as shown in Scheme 5 by reacting 4 with reaģents 8, wherein X is a good leaving group such as Cl, Br, I, or imidazole. Altematively, 4 can be reacted with an isocyanate of formula 9 in an inert solvent such as 1,2-dichloroethane to provide compounds of formula I where Z is NH.
The compounds of general formula I of the present invention may also be prepared in a convergent manner as described in Reaction Schemes 6, 7 and 8. SCHEME 6 H H Ri—ļ—N—H COOM 10 HOOC-A-N-R5 5
OR L 1 HOOC—A-N-R£ Η Η O R4 Rļ—|—N-C-A-N-R5 COOM 11
Η Η O I I II
L I -ļ-N-C-A-N-Rg COOM 11a
The carboxylic acid protected amino acid derivatives 10 are, in many cases, commercially available where M = methyl, ethyl, or benzyl esters. Other ester protected amino acids can be prepared by classical methods familiar to those skilled in the art. Some of these methods include the reaction of the amino acid with an alcohol in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid and azeotropic removal of water. Other methods includes the reaction of a protected amino acid with a diazoalkane, or with an alcohol and an acid activating aģent such as EDC, DCC in the presence of a catalyst such as DMAP and removal of the protecting group L.
Intermediates of formula 11 or 1 la, can be prepared as shown in Scheme 6 by coupling of amino acid ester 10 to amino acids of formula 6 or 7. When a urea linkage is present in 11 or 1 la, it can be introduced as illustrated in Scheme 5. -64- SCHEME7 -64- Η Η O R4 I I II I *
Ri—j—N-C-A-N-R5 COOM 11 R1—j-N-C-A-N-R5 COOH 12 Η Η O L 1 1 11 1 Rļ—j-n-c-a-n-r5 COOM 11a R1—ļ—N-C-A-N-R5 COOH 12a
Conversion of the ester 11 or 1 la to intermediate acids 12 or 12a can be achieved by a number of methods known in the art as described in Scheme 7; for example, methyl and ethyl esters can be hydrolyzed with lithium hydroxide in a protic solvent like aqueous methanol. In addition, removal of benzyl groups can be accomplished by a number of reductive methods including hydrogenation in the presence of palladium catalyst in a protic solvent such as methanol. An allyl ester can be cleaved with tetrakis-triphenylphosphine palladium catalyst in the presence of 2-ethylhexanoic acid in a variety of solvents including ethyl acetate and dichloromethane (see J. Org. Chem.. 42. 587 (1982)). SCHEME 8 Η Η O R, 1 1 11 1*
Rļ—j—N-C-A—N-R5 COOH 12a 2
F al of L F 7 -65- LV 11525
Acid 12 or 12a can then be elaborated to I or compound 7 as described in Scheme 8. Coupling of piperidines, pyrrolidines or hexahydro-lH-azepines of formula 2 to acids of formula 12 or 12a, wherein L is a suitable protecting group, is conveniently carried out under the Standard peptide coupling reaction conditions. Transformation of 7 to I is achieved by removal of the protecting group L. When R4 and/or R5 is H, substituted alkyl groups may be optionally added to the nitrogen atom as described in Scheme 4.
The 2-substituted piperidines, pyrrolidines or hexahydro-lH-azapines are either commercially available or can be prepared by literature procedures. Illustrated herein are some, but by no means ali, the methods for their preparation. SCHEME A9 H (CH2)n h R3 Α1Ϊ
-X 1) Na2W02, H2O2
2) NaCN, HCI OH>1, (CH2)n λ r3 > A14
•CN X
TiCI3
H
(CH^V-CNΜ-Χ R3 Y A2a HCI/H20 (CHiJv-COiHΜ-χ
Y A15 -66-
According to the protocol developed by S. Murahashi and T. Shiota (Tetrahedron Lett.. 28. 6469-6472 (1987)) catalytic oxidation of cyclic amines such as piperidines, pyrrolidines or hexahydro-lH-azapines with hydrogen peroxide followed by treatment with hydrogen cyanide gives a-hydroxylaminonitriles of formula AI4, which upon reduction (Murahashi, S.-I.; Kodera, Y., Tetrahedron Letters. 26. 4633-4636 (1985)) give a-aminonitriles of formula A2a. In cases where X and Y are not both hydrogen and/or n is not 2, regioisomers and diastereoisomers may arise, and they may be separated by chromatography methods. Hydrolysis of the amino nitrile under acidic or basie conditions yields the amino acid. Altematively, the hydroxylaminonitrile can be hydrolyzed first, then reduced by palladium catalyzed hydrogenation to afford the amino acid of formula A15. The amino acid and their derivatives prepared according to this method are racemic.
Altematively, the nitrile A2a can be prepared by oxidation of the compound AI3 to the imine as deseribed in the literature (Goti and Romāni in Tetrahedron Letters. 35. 6567-6570 (1994)) followed by reaction with cyanide. W can also be introduced by direct alkylation of the Boc protected compound AI3 by butyl lithium foliowed by addition of electrophiles known as the Beak alkylation (Beak and Lee J, Org. Chem., ^5, 2578-2580 (1990)). Asymmetric introduetion of W can also be aehieved by using a chiral catalyst (Kerrick and Beak, J. Am. Chem. Soe.115, 9708-9710 (1991)). SCHEME A10 H (CHŪy-C02H r3 y A15 H (CH^
Y A2
> -X LV 11525 A15 -67 r2oh, h+
H Μ-χ r3 y A2b L (CH2)VC02HM-x R, Y A16
HOBt, EDC R2R2NH L .14
{CH2)n\-COm2^2Μ-χ R3 V A2c tetrazoles other hetereocycles
(CH2j^yCN Μ-χ r3 y A17
The carboxylic acid functionality at the 2-position of compounds of formula AI5 can be converted to ester, amide, nitrile, acyl sulfonamide, and moieties as defined by W to give compound of general formula 2 according to the conventional methods well documented in the literature and known to those skilled in the art (The Practice ofPeptide Synthesis, by M. Bodanszky and A. Bodanszky, Springer-Verlag, 1984). L is an appropriate protecting group such as BOC, CBZ, etc. The carboxylic acid can also be converted into its next higher homologue, or to a derivative of the homologous acid, such as amide or ester by an Amdt-Eistert reaction. Altematively, the ester can be directly homologated by the protocol using ynolate anions described by C. J. Kowalski and R. E. Reddy in J. Org. Chem.. 57. 7194-7208 (1992). The resulting acid and/or ester can be converted to the next higher homologue, and so on and so forth. -68- SCHEME Ali
A18 A19 A2
Illustrated in Scheme Ali is a general method to introduce Y wherein X is an electron withdrawing group such as -CN, -C02R8, where Rs is alkyl, aryl, and alkyl(Cļ-C4)aryl are eitherknovvn compounds or may be prepared by methods described above or by methods analogous to those used for the preparation of known compounds. Introduction of the Y substitution can be achieved by first reacting compounds of formula AI 8 with a strong base such as potassium bis(trimethylsilyl)amide, lithium diisopropylamide following by addition of alkylating reaģents such as alkyl halides, aryl alkyl halides, acyl halides, and haloformates in a inert solvent such as THF at temperatures from -100° to room temperature. Thio deri vati ves where the sulfur is attached directly to an alkyl or an aryl group can be prepared similarly by reacting with a disulfide. The halides used in these reactions are either commercially available or known compounds in the literature can be prepared by methods analogous to those used for the preparation of known compounds. The protecting group L in compounds of formula B19 can be removed with conventional chemistry to give compounds of formula 2. -69- LV 11525 SCHEME A12
Y nr Υ 2) TMSCN (CH3)2NCOCI 1) H202 .N. .CN ζ Y 1)HC1/H20 Υ^ΧογΥ 2) H2/Pt02 r3
H N^C02H
X or Y A20 A21 A22
To prepare cis homoproline derivatives, the procedure described by Shuman et al can be used (Shuman, R. T.; Omstein, P. L.; Paschal, J. W.; Gesellchen, P. D., J. Org. Chem.. 55, 738-741 (1990)) (Scheme A12). Substituted pyridines of formula A20, many of them commercially available or prepared by literature procedures, are converted to their corresponding N-oxide by reacting with hydrogen peroxide. Reaction of the pyridine N-oxide with trimethylsilylcyanide and dimethylcarbamyl chloride gives the 2-nitrile of formula A21. If regioisomers should arise due to the presence of 3-substitution, they can be conveniently separated by chromatography. Hydrolysis of the nitrile to the acid under acidic or basie conditions followed by hydrogenation catalyzed by platinum oxide gives the piperidine carboxylic acid. The funetionalization of the carboxylic acid is described above and in part by Scheme A10.
The amino acids generated by these synthetic protocols are racemic. However, procedures for resolving RS-a-amino acids by various methods are known in the literature (Toone, E. J. and Jones, J. B. Can. J. Chem.. 65. 2722 (1987); Okamoto, S.; Hijikato, A. Biochem. Biophvs. Res. Commun.. 101.440 (1981); Greenstein, J. P.; Winitz, M. Chemistrv of the Amino Acids: Wiley: New York, 1961. Vol. 1, 715-760). Therefore, the separated R- and S- isomers can be prepared by this methodology. Altematively, the racemic piperidine, pyrrolidine and hexahydro-lH-azepine derivatives can be converted directly to growth hormone secretagogues or their intermediates, and the resulting diastereomeric mixtures can be separated at the appropriate stage by chromatography to yield the enantiomerically pure compounds. -70- SCHEME A13
Altematively, asymmetric synthesis can be carried out to synthesize optically pure piperidine, pyrrolidine and hexahydro-lH-azepine derivatives. For example, optically active piperidine-2-20 carboxylic acid derivatives AI5a, AI5b can be prepared by the aza-Diels-Alder reaction as described by Bailey et al (J. Chem. Soc. Perkin Trans L 1337-1340 (1991)). Reaction between the chiral imine A23 and the diene A24 in the presence of TFA (1 equivalent) and water (catalytic) gives the adducts A25 and A26 with good diastereoselectivity. The two 25 diastereoisomers can be separated, and each can be hydrogenated to reduce the double bond and to remove the chiral auxiliary. Ali four possible isomers can be achieved by this methodology. Illustrated here (Scheme A13) is the preparation of the two isomers A15a and A15b which have an S-configuration at the chiral center adjacent to the COOH. 30 The two R- isomers at this center can be prepared similarly using compound A26. LV 11525
The synthesis of substituted piperidines of formula 2 (n=2) has been detailed in a number of research articles. For e.g., S. Μ. N. Efange et al. (7. Med. Chem.. 2f>, 1278-1283 (1993() and M. S. Berridge et al. (J. Med. Chem.. 36.1284-1290 (1993)) have used 4-substituted-pyridine intermediates B13 to synthesize 4-substituted tetrahydropiperidines of formula B14 (L = methyl) as detailed in Scheme B9. Removal of L from piperidines of formula B14 can be carried out by a number of methods familiar to those skilled in the art, including the cyanogen bromide protocol detailed by H. Ong et al. in J. Med. Chem., 23. 981-986 (1983) and ACE-C1 method as described in R. Olofson et al. J. Org. Chem.. 23. 2795 (1984). For intermediates of formula B14, wherein L = Bn, simultaneous removal of the benzyl group and hydrogenation of the olefin can be accomplished by use of platinum or palladium catalysts in a protic solvent like methanol. Al temati vely, B13 can be directly transformed to piperidines of formula B15 (L = H) by carrying out the reduction with platinum oxide in a protic solvent such as methanol with a catalytic amount of acid. 5 -72- 10 15 L -N (ΟΗ2)Λ + £4rx TfO Y B16 SCHEME ΒΙΟ R3 - Xa - B17 [Xa= B(OH)3 or SnMe3] L (CH 2)|ΝMr* r3 y B18
B20
B19
Other methods as shown iri Scheme B10 may also be used to synthesize compounds of formula 2. For example, cross-coupling of enol 20 triflates of formula B16 (L = protecting group) where X and Y are defmed in formula I with aryl boronic acids of formula B17 (Xa = B(OH)3) or aryl or phenyl or naphthyl tin reaģents of formula B17 (Xa = SnMe3) can be accomplished with palladium (II) or palladium (0) catalysts as detailed in the review article by W. J. Scott and J. E. 25 McMurry Acc. Chem. Res.. 21.47 (1988) to give in their examples tetrahydropiperidines B18 (L = protecting group). Various methods exist for the synthesis of the enol triflate intermediates of formula B16, phenyl or naphthyl boronic acids, and phenyl or naphthyl tin reaģents of formula B17 (X = B(OH)3; SnMe3) and are familiar to those skilled in the art. 3 0 Removal of the protecting group L fumishes for example, piperidines of formula B19 (L = H). Hydrogenation of B18 follovved by removal of the protection group L also gives saturated derivatives B20. Altematively, B19 can be transformed to compounds of formula B20 by hydrogenating the olefin in the presence of platinum or palladium catalysts in a protic solvent such as methanol. -73- SCHEMEB11 L jsi (CH2), B21 LV 11525
B22 B18 H (CH2)N Mr* r3 y B19
L
(CHjS Μ-χ r3 y B20
Methods for the synthesis of substituted pyrrolidines, piperidines, and hexahydro-lH-azepines also involve addition of substituted and/or unsubstituted alkyl, cycloalkyl, phenyl or naphthyl Grignard reaģents or lithium reaģents to οχο-piperidines, oxo-pyrrolidines, or oxo-hexahydro-lH-azepines of formula B21 (L = benzyl, methyl, etc.) to give compounds of formula B22 (L = benzyl, methyl, etc.). The dehydration of the hydroxyl group of B22 (L = benzyl, methyl, etc.) to yield B18 (L = benzyl, methyl, etc.) can be carried out by treating it with strong acid or via an elimination reaction of the corresponding mesylate derived from B22 (L = benzyl, methyl, etc.). Compounds B18 can be transformed to B19 or B20 as described above. -74- SCHEMEB12 L H .N (CH2)n ^ - (CH2)nN —- Mr r3 h r3 v B21 B19
The 3,4-disubstituted piperidines, pyrrolidines and hexahydro-lH-azepines of formula B21 wherein X is an electron withdrawing group like an ester, ketone, nitrile, etc., can be further alkylated, hydroxylated, halogenated by using methods familiar to those skilled in the art. Once again, deprotection of the protecting group L can be carried out by methods familiar to those skilled in the art.
Specifīcally, ortho-substituted phenyl piperidines of of formula B22a wherein Χ,Υ = H can be prepared from the phenyl
H
B22a piperidine intermediate B23 (see S. Μ. N. Efange et al. J. Med. Chem., 26, 1278 (1993)). -75- LV 11525 SCHEME B13
B23 B24
As shown in Scheme B13, the benzyl alcohol can be oxidized to aldehyde B24 by a variety of methods familiar to those skilled in the art. Commonly used methods are manganese dioxide in an inert solvent like chloroform or the Swem protocol. A variety of functional groups can now be elaborated from B24. For example, an Emmons reaction with triethylphosphonoacetate in the presence of base gives the α,β-unsaturated ester B25. Concurrent reduction of the pyridine unit and the olefin group with a platinum or palladium catalyst in an alcoholic solvent provides the piperidine of formula B26, wherein -76- X, Υ = H. The piperidine Β26 may be derivatized to ester and acid bearing compounds of formula I wherein X and Y=H by using chemistry detailed in Schemes 1-8. Altematively, B24 can directly be transformed to a methyl ester B27, wherein X, Y = H, by oxidation of the aldehyde group to an ester with the Corey protocol (NaCN, acetic acid, Mn02, in methanol) followed by reduction of the pyridine to a piperidine with platinum or palladium catalysts in a protic solvent like methanol. The piperidine B27 can be elaborated to compounds of Formula I by using chemistry detailed in Schemes 1-8. The piperidine unit of B27 can be protected by a variety of protecting groups L familiar to those skilled in the art and the ester unit can be hydrolyzed by well documented methods to give the acid B28, wherein X, Y = H. The acid intermediate B28 can be used to prepare compounds bearing a variety of highly functionalized piperidines that can be transformed to compoundsof formula I.
Highly functionalized phenyl piperidines of formula B22, wherein X, Y = H, can be prepared by utilizing synthetic methods detailed below. LV 11525 -li
ks depicted in Scheme B14 the piperidine B26 may also serve as a key intermediate for the synthesis of a variety of piperidines of formula B22a, wherein RļO may be alkyl and aryl amides, alkyl and aryl acylsulfonamides, alkyl and aryl ureas, alkyl and aryl carbamates, etc. The piperidine nitrogen of B26 can be protected with a protecting group L (commonly used groups include BOC, CBZ, FMOC) by well documented methods and the ester unit can now be hydrolyzed with sodium or potassium hydroxide in aqueous or alcoholic media to give B29. Peptide type coupling of B29 with primary and secondary aliphatic amines, aryl amines, suitably protected amino acids, alkyl or aryl sulfonamides provides amides of formula B30, vvherein X, Y = H, followed by removal of the protecting group L. Altematively, the acid B29 can be activated with carbonyl diimidazole and subsequently reacted with primary and secondary aliphatic amines, aryl amines, suitably protected amino acids, alkyl or aryl sulfonamides in an inert solvent like tetrahydrofiiran or dimethylformamide to give amides of formula B30, wherein X, Y = H, L is on the nitrogen, and R2 and R6 may be any of the groups described in the scope of this invention. Ureas of formula B30a, wherein X, Y = H, L is on the nitrogen and R2 and R6 may be any of the -78- groups described in the scope of this invention, can be synthesized from B29 by carrying out a Curtius rearrangement and trapping the isocyanate intermediate with amines of formula HNR2R2 or HNR2R6· The protecting group L can be removed and elaborated to compounds of Formula I using chemistry presented in Schemes 1-8. -78- SCHEMEB15
The acid intermediate B29 also serves as a key intermediate for the synthesis of heterocycle bearing compounds of formula B32, wherein X, Y = H. As shown in Scheme B15, the acid B29 can be transformed to a nitrile of formula B31, wherein X, Y = H, by a 3-step sequence involving activation of the acid with ethylchloroformate in the presence of a base like triethylamine, addition of aqueous ammonia to yield a primary amide, and dehydration of the amide to a nitrile with phosphorous oxychloride in pyridine. The nitrile intermediate B31 can now be transformed to a piperidine of formula B32 vvherein X, Y = H and Rl 1 is a ΙΗ-tetrazole, by heating it with trimethyltin azide in an inert solvent like toluene or xylenes. The protecting group L may be removed and elaborated to compounds of formula I by using chemistry detailed in Schemes 1-8. -79- LV 11525 SCHEMEB16
Other heterocycle bearing piperidines of formula B32 can also be prepared from intermediate B31 as shown in Scheme B16. Treatment of the nitrile B31 with anhydrous hydrochloric acid in dry ethanol gives imino-ether of formula B33. Addition of formyl hydrazine to B33 followed by heating of the intermediate in an inert solvent like toluene provides a piperidine of formula B32, wherein X, Y = H and Ri 1 is a 1,2,4-triazole. Altematively, carbomethoxyhydrazine can be added to imino-ether B33 and cyclized to provide B32, vvherein X, Y = H and Rll is a triazolinone. Reaction of B33 with dihydroxyacetone in methanolic ammonia at high pressure gives B32, wherein X, Y = H and Rl 1 is a hydroxymethyl imidazole. The protecting group L can be removed by methods familiar to those skilled in the art and elaborated to compounds of formula I by using chemistry detailed in Schemes 1-8.
Furthermore, acids, acid chlorides, nitriles, and imino-ethers serve as key intermediates in the preparation of a number of other alkyl, phenyl, hydroxy, and amino-substituted heterocycles. Many of the methods are documented in A.R. Katrizky, Handbook of Heterocvclic -80-
Chemistrv. Pergamon Press, 1985, New York, New York, and may be used to synthesize a variety of heterocycle bearing compounds. SCHEMEB17
Other applicable routes for the synthesis of mono- and di-substituted pyrrolidines, piperidines , and hexahydro-lH-azepines of formula II (n=l or 2) are known in the literature. For example, J. J. Plati 20 and W. Wenner (7. Org. Chem.. 14. 543 (1949)) have demonstrated that the ketoamine intermediate B34 may be elaborated to B35 (n=l, 2, 3) under aldol condensation conditions. Dehydroxylation of B35 can be achieved by a number of methods including a catalytic hydrogenation method that utilizēs palladium catalysts in a protic solvent like methanol. 25 Removal of L from B36 can be carried out methods, including the ACE-C1 method as described in R. Olofson et al. (J. Org. Chem.. 43. 2795 (1984)). 30 -81 - LV 11525 SCHEME B18 5
R3MgBr CIC02Et C02Et
CuCI 10
15 20 25
The synthesis of 3,4-disubstituted piperidines of formula 2 (n=2) can be conveniently prepared by literature procedures. Illustrated below is one of these general methods. G. T. Borrett has demonstrated the synthesis of ris 3,4-disubstituted piperidine B39 (US Patent 4,861,893) from the commercially available ethyl nicotinate and the Grignard reaģent R3MgBr where R3 is defined in formula I. The ester functionality of B38 may be further modified through conventional chemistry to provide other functional groups X as defined in the scope of the invention. Illustrated here are some, but by no means ali, the methods available to preparē functional groups X. For example, the ester of B38 can be hydrolyzed to give the corresponding carboxylic acid B39 (X=C02H); B39 may then be converted to amides (X=CONR2R2) by a simple peptide-type coupling reaction, to ureas or carbamates (X= NC(0)NR2R2, NC(0)0R2) by the Curtius rearrangement (Smith, Ore. React.. 3, 337 (1946)) followed by trapping of the isocyanate intermediate with amines or alcohols or to an hydroxymethyl unit (X=CH20R2) by borane reduction. The acid B39 can also be converted to a nitrile and then elaborated to heterocyclic compounds (X=tetrazolyl, triazolyl, triazolinolyl etc.) by the procedures described in Schemes B15 and B16. The carboxylic acid B39 (X=C02H) can also be converted into its higher homologue B39 (X=CH2C02H) by an Amdt-Eistert reaction and further derivatized by methods which have been described above. 30 -82- SCHEMEB19 1 Ν
C02Et ds r3 Β38 base Μ L I Ν
X trans R3 B40 R3 B41
The cis 3,4-disubstituted piperidines B38 can be converted to trans 3,4-disubstituted piperidines B40 as shown in Scheme B19 by treating B38 with a catalytic amount of base such as sodium ethoxide in protic solvent. Once again, the ester functional group of B40 can be further modified by methods familiar to those skilled in the art, including the procedures described in Scheme B18. The protecting group L from compounds of formulas B39 and B41 can be removed through conventional chemistry and elaborated to compounds of formula I by using chemistry described above. -83- LV 11525 SCHEME B20
piperidines of formula B43 can be prepared by the addition of B42 to ethyl nicotinate by the procedure of G.T. Borrett (U.S. Patent No. 4,861,893). The acetal protecting group can be removed by a number of methods familiar to those skilled in the art. The resulting aldehyde B44 serves as a key intermediate for the synthesis of highly functionalized 3,4-disubstituted piperidines. The aldehyde B44 can be oxidized to the corresponding carboxylic acid B45 and then further elaborated to a variety of functional groups such as amides, ureas, carbamates, acylsulfonamides and etc. Some examples of these transformations are discussed in connection with Scheme B14. -84- SCHEME B21
L
I
Compound B44 can also be converted to an α, β-unsaturated ester or nitrile by an Emmons reaction. The resulting unsaturated ester or nitrile can be hydrogenated using a catalytic amount of palladium or platinum under hydrogen atmosphere. The diester B45 (X=C02Et, E=C02Et) as shown in Scheme B21 can be selectively hydrolyzed to corresponding acid B45 (X=C02Et, E=C02H) which can be further elaborated to variety of functional groups by a number of methods. Compounds of formula B31 (X=C02Et, E=CN) can be transformed to compounds of formula 32 (X=C02Et, Y=H, Rļ 1=1H-tetrazole) by heating B31 with trimethyl azide in toluene. Altemately, the nitrile intermediate B31 (for example, with X=C02Et, E=CN) may also serves as a synthetic precursor for the synthesis of heterocycle bearing compounds of formula B32 (X=C02Et). Many of the synthetic methods as noted above in A.R. Katrizky, Handbook of Heterocyclic Chemistry, Pergamon Press, 1985, New York, New York, and are discussed in connection vvith Scheme B16.
The 3,4-disubstituted compounds 2 generated by these synthetic protocols are racemic. Mono and disubstituted pyrrolidines and -85- LV 11525 hexahydro-lH-azepines 2 generated by these synthetic protocols are also racemic. Chiral intermediates of formula 2 are available by numerous methods including by the classical resolution of racemates. For example resolution can be achieved by the formation of diastereomeric salts of racemic amines with optically active acids such as D- and L- tartaric acid. The determination of the absolute stereochemistry can be accomplished in a number of ways including X-ray crystallography of a suitable crystalline derivative such as a D- or L- tartaric acid salt. Altematively, asymmetric synthesis can be carried out to synthesize optically pure compounds.
Furthermore, the racemic intermediates of formula 2 can be derivatized with chiral reaģents and these products may be separated by chromatography and chiral compounds of formula 2 may be regenerated from them by hydrolysis, or as stated earlier, racemic intermediates of formula 2 can be converted directly to growth hormone secretagogues, and the resulting diastereomeric mixtures can be separated by chromatography to yield the enantiomerically pure compounds. SCHEME C9
,N
Hydrogenation ‘X(orY)
H N
C13 C13a X(or Y) 3-Monosubstituted piperidines of formula C13 can be prepared by the reduction of pyridine derivatives or their salts by hydrogenation in a suitable organic solvent such as water, acetic acid, alcohol, e.g. ethanol, or their mixture, in the presence of a noble mētai catalyst such as platinum or an oxide thereof on a support such as activated carbon, and conveniently at room temperature and atmospheric pressure or under elevated temperature and pressure. 3-Monosubstituted piperidines can also be prepared by modification of the X or Y moiety of the existing 3-monosubstituted piperidines. -86- -86- SCHEME C9A Bn 1) BH^HF H u X / '—LC02Me 2) H^Pd/C 3) HCI/ROH C13b 3-Monosubstituted pyrrolidines are commercially available or can be conveniently prepared by literature procedures. Shown in Scheme C9A is an example of the preparation of these compounds via pyrrolidine-3-carboxylic acid ester. The commercially available compound methyl l-benzyl-4-oxo-3-pyrrolidinecarboxylate is reduced by borane (J. Chem. Soc.. 24. 1618-1619). Removal of the benzyl group by catalytic hydrogenolysis followed by ester exchange in an appropriate alcohol medium such as ethyl alcohol in the presence of acid gavē the compound C13b. The ester functionality may be further modified through conventional chemistry to other groups as defined by X. 3-Monosubstituted pyrrolidines may also be prepared by catalytic hydrogenation of 3-substituted pyrroles.
SCHEME C9B
H N co2r
H
N
\ /~~C02H C13c
Hexahydro-lH-azepines are commercially available or may be prepared by the literature procedure. Hexahydro-lH-azepine-3-carboxylic acid (Krogsgaard-Larsen, P. et al., Acta. Chem. Scand.. B32. 327, (1978)) is esterified in an alcohol solvent in the presence of acid. The ester functionality may be further modified through conventional chemistry to other groups vvithin the definition of X. -87- LV 11525 SCHEMEC10
Protection C13
C14
X
Base/ activated Y-
removal of L
C15
Illustrated in Scheme CIO is a general way to prepare di-substituted piperidines, pyrrolidines, and hexahydro-lH-azepines. Compounds of Formula C13 wherein X is an electron withdrawing group such as -CN, -CO2R8» where Rs is alkyl, aryl, and (Ci-C4alkyl)aryl are known compounds or may be prepared by methods analogous to those used for the preparation of such known compounds. The secondary amine of compounds of Formula C13 may be first protected by a protecting group L such as BOC and CBZ using the conventional techniques. Introduction of the Y substitution can be achieved by first reacting compounds of Formula C14 with a strong base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide following by addition of alkylating or acylating reaģents such as alkyl halides, aryl alkyl halides, acyl halides, and haloformates in a inert solvent such as THF at temperatures from -100° to room temperature. Thio derivatives where the sulfur is attached directly to an alkyl or an aryl group can be prepared similarly by reacting with a disulfide. The halides used in these reactions are either commercially available or known compounds in the literature or may be prepared by methods analogous to those used for the preparation of known compounds. The protecting group L in compounds of formula C15 may be removed with conventional chemistry to give compounds of Formula 2. -88- SCHEMEC11
EtOgC^CN Y C16 alkylation
EtOgC^CN γ' (^Η2)η
17 0H2CI reduction r (CH2)n Y C2a ‘C02Et
Altemative ways of preparing compounds of Formula 2 include construction of the ring itself (Jacoby, R. L. et al, J. Med. Chem.. 12, 453-455, (1974)). Alkylation of the cyanoacetates of general formula C16, which are commercially available or may be prepared from literature procedures, with alkyl dihalides such as l-bromo-2-chloroethane or l-bromo-3-chloropropane yields the chloride C17. Reduction of the nitriles C17 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, vvhich upon refluxing in ethanol to give compounds of Formula 2a.
Et02C^CN Y C16
SCHEMEC12 Br(CH2)nC02Et Et02C or CH2CHC02Et CN (CH2)n C18 C02Et
reduction of CN
HrN. (CH2)n-C2a Y reduction 'C02Et H°γΝ· (CH2)n- C19 'C02Et
Altematively, the cyanoacetates of general formula C16 may be alkylated with an ethoxycarbonylalkyl bromide or reacted with ethyl -89- LV 11525 acrylate to give compounds of Formula C18. Reduction of the nitriles C18 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, which upon refluxing in ethanol gives lactam 09. Reduction of the lactam C19 by borane gives compounds of Formula C2a. SCHEME 03
Et02C
Y C02Et Y C20
Et02C C02EtΥί C21 CN (CH2)n reduction H n(H2C)'N^ reduction
n(H2C) L
H
.N Y C2a C02Et Y C22 O C02Et
Altematively, a malonate of general formula C20 may be alkylated with cyanoalkyl bromide or can be reacted with acrylonitrile to form compounds of formula C21. Reduction of the nitriles C21 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, which upon refluxing in ethanol gives lactam C22. Reduction of the lactam C22 by borane gives compounds of formula C2a.
-90- SCHEMEC14 L L L JM. >)γΛ OH- —(CH2£\ - (CHŪ C02H
C02Et CH2Br2 .Rases
Arndt-Eistert reaction CH2C02R or amide
CONR2R3 or ester
The X, Y functionalities in compounds of general structure C15 may be further elaborated to groups not accessible by direct alkylation. For example in Compound C15 when X = C02Et the ester (provided that this is the only ester group in the molecule) can be saponified to the carboxylic acid, which can be further derivatized to amides or other esters. The carboxylic acid can be converted into its next higher homologue, or to a derivative of the homologous acid, such as amide or ester by an Arndt-Eistert reaction. Altematively, the ester can be directly homologated by the protocol using ynolate anions described by C. J. Kowalski and R. E. Reddy in J. Orp. Chem.. 57, 7194-7208 (1992). The resulting acid and/or ester may be converted to the next higher homologue, and so on and so forth. The protecting group L may be removed through conventional chemistry. -91- SCHEME C15 L ,N (CH2)n \_ reduction
-C02Et Y C15a L .N (CH2)n acylation — CHoOH V C18 1) MsCI/TEA 2) NaN3 L (CH2)n \_ —CH202CR2 Y C19 LV 11525
L ,N (CH^ C20 Y CH2N3
L
reduction (Ch2)N CH2NH2
C21 Y
The ester in C15a may be reduced to an alcohol 08 in a suitable solvent such as THF or ether with a reducing aģent such as DIBAL-H and conveniently carried out at temperatures from -100°C to 0°C. The alcohol may be acylated to Compound C19 in a suitable solvent such as dichloromethane using an acyl halide or acid anhydride in the presence of a base such as triethyl amine (TEA). The hydroxy group in 08 may also be converted to a good leaving group such as mesylate and displaced by a nucleophile such as cyanide, a thiol or an azide. Reduction of the azide in compounds of Formula C20 to an amine C21 can be achieved by hydrogenation in the presence of a noble mētai such as palladium or its oxide or Raney nickel in a protic solvent such as ethanol. The nitrile can be reduced to afford the homologous amine. The amine of Formula C21 may be further elaborated to amides, ureas sulfonamides as defined by X through conventional chemistry. The protecting group L may be removed through conventional chemistry. -92- SCHEMEC16 Βη Ν (CH2)n ^ — C28
Βη<ch2)!N 1-—ΟΗ C29 Y(orX) acylation Η(CH2)n ' Βη deprotection
OCOR Υ (or X) C2b --OCOR C30Y (0Γ X)
In cases where oxygen is directly attached to the ring, a convenient method involves the addition reaction by an activated form of an alkyl, aryl, alkylaryl group, such as lithium reaģent, Grignard reaģents, and the like with a ketone of general formula C28, which is commercially available. Further derivatization of the resulting hydroxy group by acylation, sulfonylation, alkylation, and the like gives compounds as defined by Y or X through conventional chemistry. Removal of the benzyl protective group may be carried out under the usual conditions to give compounds of general formula C2b. Shown in Scheme C16 is a general example of acylations. -93- LV 11525 SCHEMEC17 1)(COCI)2 L -N. - (CH2)n 2) NaN3 \_ 3) reflux/toluene h2o or 1) BnOH 2) Pd/C , N=C=0
C02H Y C23 amines ^or alcohol ureas or carbamates
(CHA . acy|alion (ch2K (-NHCOR deprotection ^ -( NH2
C2c Y C32 Y
In cases where a nitrogen-substituted group is directly attached to the ring, a convenient method is to use the Curtius rearrangement on the acid C23 to afford the isocyanate C31. Addition of amines or alcohols give ureas or carbamates respectively which can be deprotected to remove L to give special cases of compounds of formula C2. Conversion of the isocyanate to amine by hydrolysis gives compound C32. Further derivatization of the resulting amine group by acylation, sulfonylation, alkylation, and the like to give compounds as defined by Y or X can be done through conventional chemistry. Removal of the protective group L may be carried out under the usual conditions to give compounds of general formula C2c. Shown in Scheme C17 is a general example of acylations. -94- SCHEMEC18 -94-
Bu3SnN2
NaOH
DMSO H202
L
For compounds that are not readily obtainable by direct alkylation as shown in Scheme CIO, modifīcations of easily obtainable compounds of general formula C15 may be conducted to achieve the desired substitution through conventional chemistry. For example, compounds with Y being hydroxybenzyl may be prepared by demethylation of the corresponding compound wherein Y is methoxybenzyl. Similarly, compounds with Y being aminobenzyl may be prepared by reduction of the corresponding compound wherein Y is nitrobenzyl. Shown in Scheme C18 is an example of a procedure that uses nitrile as a starting point for the preparation of compounds with different substitutions. Removal of the protective group L gives compounds of general formula C2 as described in Scheme CIO.
Compounds of the general formula C2 prepared in this way are racemic when X and Y are not identical. Resolution of the two enatiomers can be conveniently achieved by classical crystallization -95- LV 11525 methods by using a chiral acid such as L- or D-tartaric acid, (+) or (-)-10-camphorsulfonic acid in a suitable solvent such as acetone, water, alcohol, ether, acetate or their mixture. Altematively, the racemic amine C2 can be reacted with a chiral auxiliary such as (R) or (S)-O-acetylmandelic acid followed by chromatographic separation of the two diastereomers, and removal of the chiral auxiliary by hydrolysis. Altematively asymmetric alkylation can also be utilized for the synthesis of optically active intermediate by introducing a removable chiral auxiliary in X or in place of L with subsequent chromatographic separation of diastereomers.
In cases where a sulfide is present in the molecule, it may be oxidized to a sulfoxide or to a sulfone with oxidizing aģents such as sodium periodate, m-chloroperbenzoic acid or Oxone® in an solvent such as dichloromethane, alcohol or water or their mixtures.
The compounds of the present invention may also be prepared from a variety of substituted natūrai and unnatural amino acids of formula D46. The preparation of many of these acids is described in US Patent No. 5,206,237. The preparation of these intermediates in racemic form is accomplished by classical methods familiar to those skilled in the art (Williams, R. M. "Synthesis of Optically Active a-Amino Acids" Pergamon Press: Oxford, 1989; Vol. 7). Several methods exist to resolve (DL)-
H R R1--Nv
H
C02H D46 amino acids. One of the common methods is to resolve amino or carboxyl protected intermediates by crystallization of salts derived from optically active acids or amines. Altematively, the amino group of carboxyl protected intermediates may be coupled to optically active acids by using chemistry described earlier. Separation of the individual diastereomers either by chromatographic techniques or by crystallization followed by hydrolysis of the chiral amide fumishes resolved amino acids. Similarly, amino protected intermediates may be converted to a -96- mixture of chiral diastereomeric esters and amides. Separation of the mixture using methods described above and hydrolysis of the individual diastereomers provides (D) and (L) amino acids. Finally, an enzymatic method to resolve N-acetyl derivatives of (DL)-amino acids has been reported by Whitesides and covvorkers in J. Am. Chem. Soc. 1989, 111. 6354-6364.
When it is desirable to synthesize these intermediates in optically pure form, established methods include: (1) asymmetric electrophilic amination of chiral enolates (J. Am. Chem. Soc. 1986, 108. 6394-6395, 6395-6397, and 6397-6399), (2) asymmetric nucleophilic amination of optically active carbonyl derivatives, (J. Am. Chem. Soc. 1992, 114. 1906; Tetrahedron Lett. 1987, 28, 32), (3) diastereoselective alkylation of chiral glycine enolate synthons (J. Am. Chem. Soc. 1991, 113. 9276; J. Org. Chem. 1989, £4, 3916), (4) diastereoselective nucleophilic addition to a chiral electrophilic glycinate synthon (J. Am. Chem. Soc. 1986, 108. 1103), (5) asymmetric hydrogenation of prochiral dehydroamino acid derivatives ("Asymmetric Synthesis, Chiral Caīalysis\ Morrison, J. D., Ed; Academic Press: Orlando, FL, 1985; Vol 5), and (6) enzymatic syntheses (Angew. Chem. Int. Ed. Engl. 1978, 77, 176). -97- LV 11525 SCHEMED14 Ph Ph
Ph 2)PdCI2/H2
D49 5 10 15 For example, alkylation of the enolate of diphenyloxazinone D47 (J. Am. Chem. Soc. 1991,113.9276) with cinnamyl bromide in the presence of sodium bis(trimethylsilyl)amide proceeds smoothly to afford D48 which is converted into the desired (D)-2-amino-5-phenylpentanoic acid D49 by removing the N-t-butyloxycarbonyl group with 2 0 trifluoroacetic acid and hydrogenation over a PdCl2 catalyst (Scheme D14). SCHEME D15 25
H I C02H
NaH/DMF Ar-CH2-X H i
co2h D50 D51
Intermediates of formula D46 which are 0-benzyl-(D)-serine derivatives D51 are conveniently prepared from suitably substituted benzyl halides and N-protected-(D)-serine D50. The protecting group L is conveniently a BOC or a CBZ group. Benzylation of D64 can be achieved by a number of methods well known in the 30 -98- literature including deprotonation with two equivalents of sodium hydride in an inert solvent such as DMF followed by treatment with one equivalent of a variety of benzyl halides (Synthesis 1989, 36) as shown in Scheme D15.
The 0-alkyl-(D)-serine derivatives may also be prepared using an alkylation protocol. Other methods that could be utilized to prepare (D)-serine derivatives of formula D51 include the acid catalyzed benzylation of carboxyl protected intermediates derived from D50 with reaģents of formula ArCH20C(=NH)CCl3 (0. Yonemitsu et al·, Chem. Pharm. Buli. 1988, 36, 4244). Altematively, alkylation of the chiral gylcine enolates (7. Am. Chem. Soc. 1991,113, 9276; 7. Org. Chem. 1989, 54, 3916) with ArCH20CH2X where X is a leaving group affords D51. In addition D,L-0-aryl(alkyl)serines may be prepared and resolved by methods described above.
It is noted that in some situations the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unvvanted reaction products.
The utility of the compounds of the present invention as growth hormone secretagogues may be demonstrated by methodology known in the art, such as an assay described by Smith , et al., Science. 260. 1640-1643 (1993) (see text of Figurē 2 therein). In particular, ali of the compounds prepared in the following examples had activity as growth hormone secretagogues in the aforementioned assay. Such a result is indicative of the intrinsic activity of the present compounds as growth hormone secretagogues.
The growth hormone releasing compounds of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary Ievel. This includes use in the evaluation of many factors thought or known to influence grovvth hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting States. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that -99- -99- LV 11525 somatostatin inhibits grovvth hormone release. Other hormones that are important and in need of study as to their effect on gro\vth hormone release include the gonadal hormones, e.g., testosterone, estradiol, and progesterone; the adrenal hormones, e.g., cortisol and other corticoids, epinephrine and norepinephrine; the pancreatic and gastrointestinal hormones, e.g., insulin, glucagon, gastrin, secretin; the vasoactive peptides, e.g., bombesin, the neurokinins; and the thyroid hormones, e.g., thyroxine and triiodothyronine. The compounds of Formula I can also be employed to investigate the possible negative or positive feedback effects of some of the pituitary hormones, e.g., growth hormone and endorphin peptides, on the pituitary to modify growth hormone release. Of particular scientific importance is the use of these compounds to elucidate the subcellular mechanisms mediating the release of growth hormone.
The compounds of Formula I may be administered to animals, including man, to release growth hormone in vivo. For example, the compounds can be administered to commercially important animals such as svvine, cattle, sheep and the like to accelerate and increase their rāte and extent of growth, to improve feed effīciency and to increase milk production in such animals. In addition, these compounds can be administered to humāns in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone. For example, the compounds of Formula I can be administered in vivo to children. Serum samples taken before and after such administration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly determining the ability of the patient's pituitary to release grovvth hormone.
Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise an anabolic aģent in addition to at least one of the compounds of Formula - 100 - I or another composition which exhibits a different activity, e.g., an antibiotic growth permittant or an aģent to treat osteoporosis or in combination with a corticosteroid to minimizē the catabolic side effects or with other pharmaceutically active materiāls wherein the combination enhances efficacy and minimizēs side effects.
Growth promoting and anabolic aģents include, but are not limited to TRH, diethylstilbesterol, estrogens, β-agonists, theophylline, anabolic steroids, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Patent No. 4,411,890. A stili further use of the growth hormone secretagogues of this invention is in combination with other growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6, GHRP-1 as described in U.S. Patent Nos. 4,411,890 and publications WO 89/07110, WO 89/07111 and B-HT920 as well as hexarelin and the newly discovered GHRP-2 as described in WO 93/04081 or growth hormone releasing hormone (GHRH, also designated GRF) and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 or a- adrenergic aginists such as clonidine or serotonin 5HTID agonists such as sumitriptan or aģents vvhich inhibit somatostatin or its release such as physostigmine and pyridostigmine.
As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. The administration of the compounds of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself. These varied uses of the present compounds thus may be summarized as follows: stimulating growth hormone release in elderly humāns; treating grovvth hormone deficient adults; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis; stimulation of the immune system, acceleration of \vound healing; accelerating bone fracture repair; treatment of growth retardation; treating acute or chronic rēnai failure or insufficiency; -101 - LV 11525 treatment of physiological short stature, including growth hormone deficient children; treating short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with Prader-Willi syndrome and Tumer's syndrome; accelerating the recovery and reducing hospitalization of bum patients or following major surgery such as gastrointestinal surgery; treatment of intrauterine growth retardation, and skeletal dysplasia, treatment of peripheral neuropathies; replacement of growth hormone in stressed patients; treatment of osteochondrody-splasias, Noonans syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing, and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic response after a major operation; treating malabsorption syndromes; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; accelerating weight gain and protein accretion in patients on TPN (total parenteral nutrition); treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction and to prevent and treat gastric and duodenal ulcers; to stimulate thymic development and prevent the age-related decline of thymic function; adjunctive therapy for patients on chronic hemodialysis; treatment of immunosuppressed patients and to enhance antibody response following vaccination; increasing the total lymphocyte count of a human, in particular, increasing the T4/T8-cell ratio in a human with a depressed T4/T8-cell ratio resulting, for example, from physical trauma, such as closed head injury, or from infection, such as bacterial or virai infection, especially infection with the human immunodeficiency virus; improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, rēnai hemeostasis in the frail elderly; stimulation of osteoblasts, bone remodelling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock; and stimulation of wool growth in sheep. Further, the instant compounds are useful for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock. - 102-
In particular, the instant compounds are useful in the prevention or treatment of a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuāls vvith a depressed T4/T8 celi ratio; hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; obesity; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or bums, in a patient in need thereof.
It will be known to those skilled in the art that there are numerous compounds now being used in an effort to treat the diseases or therapeutic indications enumerated above. Combinations of these therapeutic aģents some of which have also been mentioned above with the growth hormone secretagogues of this invention will bring additional, complementary, and often synergistic properties to enhance the grovvth promotant, anabolic and desirable properties of these various therapeutic aģents. In these combinations, the therapeutic aģents and the growth hormone secretagogues of this invention may be independently present in dose ranges from one one-hundredth to one times the dose Ievels which are effective when these compounds and secretagogues are used singly.
Combined therapy to inhibit bone resorption, prevent osteoporosis and enhance the healing of bone fractures can be illustrated by combinations of bisphosphonates and the grovvth hormone secretagogues of this invention. The use of bisphosphonates for these Utilities has been revievved, for example, by Hamdy, N.A.T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinol. Metab.. 4, 19-25 (1993). Bisphosphonates vvith these Utilities include alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, ΥΜ-175, clodronate, pamidronate, and BM-210995. According to their potency, oral daily dosage Ievels of the bisphosphonate of betvveen 0.1 mg and 5 g and daily dosage Ievels of the grovvth hormone secretagogues of this invention of betvveen 0.01 mg/kg to 20 mg/kg of body vveight are administered to patients to obtain effective treatment of osteoporosis.
The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or -103- -103- LV 11525 subcutaneous injection, or implant), nasal, vaginai, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pilis, povvders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normai practice, additional substances other than inert diluents, e.g., lubricating aģents such as magnesium stearate. In the case of capsules, tablets and pilis, the dosage forms may also comprise buffering aģents. Tablets and pilis can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, Solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting aģents, emulsifying and suspending aģents, and svveetening, flavoring, and perfuming aģents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous Solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and com oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing aģents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incoīporating sterilizing aģents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginai administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. - 104-
Compositions for nasal or sublingual administration are also prepared with Standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount 5 of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage Ievels of betvveen 0.0001 to 100 mg/kg. of body weight daily are administered to patients and animals, e.g., 10 mammals, to obtain effective release of growth hormone.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. As will be apparent, the examples and intermediates designated "A" correspond to the compounds of the first 15 embodiment, those designated "B" correspond to the compounds of the second embodiment, and those designated "C" correspond to the compounds of the third embodiment. INTERMEDIATE 1
20 25
Step A:
To a solution of the commercially available N-t-BOC-D-tryptophan (25.0 g, 82.2 mmol), benzyl alcohol (10.2 mL, 98.6 mmol), and DMAP (100 mg) in dichloromethane (200 mL) at 0°C, was added EDC (17.4 g, 90.4 mmol) in several portions over a one hour period. The 30 -105 - -105 - LV 11525 reaction mixture was stirred at room temperature for six hours and was poured into water (200 mL), and the organic layer was separated. The organic solution was washed with a mixture of brine and 3 N hydrochloric acid, dried over anhydrous magnesium sulfate, filtered and concentrated to give a thick oil, which solidified upon standing.
To a solution of this oil in 30 mL of dichloromethane was added 20 mL of TFA and stirred for lh. The reaction mixture was concentrated, neutralized carefully with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (2X100 mL). The combined organic solution was washed with brine (100 mL), passed through a short column of silica gel eluting with 5-10% methanol in dichloromethane to give 23.2 g of the amine as an oil after evaporation.
To a solution of the above product, HOBT (10.6 g, 78.8 mmol) and N-BOC-a-methyl alanine (19g, 94.5 mmol) in 200 mL of dichloromethane, was added EDC (19.5 g, 0.102 mol) in several portions at 0°C. After 5 minūtes, the clear reaction mixture became milky. After stirring at room temperature ovemight, the reaction mixture was poured into 200 mL of water and the organic layer was separated. The organic solution was washed with brine, and with a brine and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give a thick oil, which was purified by flash chromatography eluting with a gradient of 10-40% ethyl acetate in hexane to give the desired material (28.7 g). 1H NMR (CDCI3, 200 MHz) δ 8.48 (br.s, 1H), 7.54 (br.d, 1H), 7.38-7.23 (m, 3H), 7.19 (br.d, 2H), 7.15-7.00 (m, 1H), 6.90 (d, 1H), 6.86 (d, 1H), 5.06 (br.s, 2H), 4.95 (ddd, 1H), 3.30 (2dd, 2H), 1.40 (s, 15H) -106-
Step C: 10 A solution of the material from Step B (28.7g) in 200 mL of ethanol was stirred at RT under a H2 balloon for 20 minūtes in the presence of 10% palladium on carbon (2 g). The catalyst was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give the acid as a slightly pink foam (23.3 g). 1H NMR (CD3OD, 400 MHz) δ 7.56 (d, J=8 Hz, 1 H), 7.31 (dd, J=l, 8 Hz, 1 H), 7.09 (s, 1 H), 7.07 (dt, J=l, 7 Hz, 1 H), 6.98 (dt, J=l, 7 Hz, 1 H), 4.69 (t, J=6 Hz, 1 H), 3.34-3.23 (m, 2 H), 1.35 (s, 3 H), 1.34 (s, 9 H), 1.29 (s, 3 H). 15
FAB-MS calc. for C20H27N3O5 : 389 ; Found 390 (M+H), 290 (M+H-100 (BOC)).
INTERMEDIATE 2 H ^NHBoc 20
OH
Following the procedures for the preparation of Intermediate 1 using N-t-Boc-0-Benzyl-D-serine in the place of N-t-BOC-D-tryptophan gavē Intermediate 2. 25 FAB-MS calc. for C19H28N2O6 : 380 ; Found 381 (M+H), 325 (M+H-56 (t-Bu)), 281 (M+H-100 (BOC)). 30 - 107- INTERMEDIATE 3
LV 11525
Step A: ('DLVN-acetvl-2-amino-5-phenvlpentanoic acid
To a solution of sodium (2.3 g, 0.1 mol) in ethanol (60 mL) under nitrogen at room temperature, was added diethyl acetamidomalonate. The mixture was stirred at room temperature for one 10 hour, and then l-bromo-3-phenylpropane was added dropwisely. After the addition, the mixture was stirred at room temperature for two hours, then refluxed ovemight. It was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with sodium bicarbonate in water, dried over MgS04 and 15 evaporated to give an intermediate (32.5 g, 97%). lH NMR (CDC13,400MHz) 7.26-7.10 (m, 5 H); 6.75 (br. s, 1 H); 4.19 (q, J=7 Hz, 4 H); 2.58 (t, J=7.9 Hz, 2 H); 2.39-2.35 (m, 2 H); 2.00 (s, 3 H); 1.43-1.39 (m, 2 H); 1.20 (t, J=7 Hz, 6 H).
The product above was suspended in 190 mL of 2.5 N 20 NaOH in water and refluxed for two hours. The mixture was cooled to 0°C, and it was carefully neutralized with 6 N HC1 to pH2. The precipitate was collected using a sintered glass funnel and vvashed with a small amount of cold water and air dried. The solid was then suspended in 300 mL of water and refluxed for four hours. The solution was cooled 25 and acidified to pHl and the solid was collected by filtration (15.3 g, 67%). lH NMR (CD30D, 400MHz) 7.26-7.12 (m, 5 H); 4.90-4.37 (m, 1 H); 2.65-2.60 (m, 2 H); 1.97 (s, 3 H); 1.87 -1.82 (m, 1 H); 1.73-1.65 (m, 3 H). 30 Step B: (DLN-acetvl-2-amino-5-phenvlpentanoic acid
The racemic intermediate from the previous step (10 g, 42.5 mmol) and CoC13-6H20 were dissolved in 21 ml of 2 N KOH and 200 mL of water at 40°C, and the pH of the solution was adjusted to 8 by the addition of the several drops of 2 N KOH. Then acylase I (Aspergillus sp, 0.5 u/mg, from Sigma; 0.9 g) was added with vigorous stirring. The -108- reaction mixture was stirred for one day at 40°C and the pH was ķept at 8 by the addition of a few drops of KOH. The solid which formed was filtered off. The filtrate was acidified by 3 N HC1 to pH2, and was extracted with ethyl acetate (200 mLX4). The organic extracts were 5 combined and evaporated to give a white solid (4.64 g, 46%) lH NMR (CD30D, 400MHz) 7.26-7.12 (m, 5 H); 4.90-4.37 (m, 1 H); 2.65- 2.60 (m, 2 H); 1.97 (s, 3 H); 1.87 -1.82 (m, 1 H); 1.73-1.65 (m, 3 H).
Step C: (T)VN-t-Boc-2-amino-5-phenvIpentanoic acid 10 The intermediate from step B (4.2 g, 17.8 mmol) was suspended in 2 N HC1 (100 mL) and refluxed for two hours. The reaction mixture was evaporated in vacuo to remove water and hydrochloric acid to yield a white solid. To a solution of this solid in 50 mL of water, was added 3 N NaOH until the pH 11, then di-t-butyl dicarbonate (4.66 g, 15 21.4 mmol) was added with vigorous stirring. After four hours, the reaction mixture was acidified to pH2 with 3 N HC1 and it was extracted with ethyl acetate (100 mLX3). The organic extracts were combined and evaporated to give a white solid (6.56 g, crude) which was used without purification. 20 lH NMR (CD30D, 400MHz) 7.26-7.12 (m, 5 H); 4.11-4.08 (m, 1 H); 2.65- 2.60 (m, 2 H); 1.83-1.62 (m, 4 H); 1.43 (s, 9 H).
Step D:
Following the procedures for the preparation of Intermediate 1 using (D)-N-t-Boc-2-amino-5-phenylpentanoic acid in the place of N-t-30 B OC-D-tryptophan gavē Intermediate 3. lH NMR (CDCI3,400MHz) 7.24-7.20 (m, 2H), 7.15-7.04 (m, 3H), 4.60-4.55 (m, 1H), 2.62-2.55 (m, 2H), 2.00-1.86 (m, 1H), 1.78-1.60 (m, 3H), 1.50 (s, 6H), 1.30 (s, 9H). -109- LV 11525 ΕΧΑΜΡΙ.Ε Α1
Step Α:
3 rVr* C=0 O ,N^ ^C02Et NHBoc
3 NHBoc C=0 O i cr N. .C02Et
To a solution of ethyl (dl) pipecolinate (1 g), HOBT (860 mg) and Intermediate 1 (2.47 g) in dichloromethane (80 mL) at 0°C, was added EDC (2.3 g). The reaction mixture was stirred at room temperature ovemight. The solution was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate; then filtered and concentrated to give a crude product. The crude product was purified by MPLC eluting with 60% ethyl acetate in hexane to give the product as a mixture of two diastereomers (2.79 g). Separation of 500 mg of the mixture by MPLC eluting with 50% ethyl acetate in hexane yielded the two individual diastereomers. The diastereomer which came out of the column first was designated as dļ (187 mg) and the stereochemistry of the pipecolinic acid ester was subsequently shown to be R. The one vvhich came out last was designated as d2 (116 mg) and the stereochemistry of the pipecolinic acid ester in it is S. In addition, there were mixed fractions which were combined and evaporated to yield 190 mg of a mixture of dl and d2. dl: FAB-MS calc. for C28H40N4O6: 528 ; Found: 529 (M+H) d2: FAB-MS calc. for C28H40N4O6: 528 ; Found: 529 (M+H) - 110-
Step B:
A solution of the compound di from Step A (140 mg) in 10 ethyl acetate (5 mL) was cooled to 0°C. While stirring, hydrogen chloride gas was bubbled into the mixture until saturation occurred. The reaction was stirred for 15 minūtes. The solution was then concentrated to remove ethyl acetate. The residue was then redissolved in dichloromethane and hexane followed by evaporation in vacuo to afford the product as a solid 15 (110 mg). FAB-MS calc. for C23H32N4O4: 428 ; Found: 429 (M+H) iHNMR (400 MHz, CD3OD): compound exists as a mixture of rotamers (about 2:1). 7.57 (d, 1 H), 7.36 &7.32 (2 d, 1 H), 7.14-7.00 (m, 3 H), 20 5.30-5.20 (m), 5.17-5.13 (m), 4.36 (d), 4.21 (q, J=7 Hz), 4.13 (q, J=7 Hz), 4.00 (md), 3.35-3.04 (m), 2.60 (dt), 3.30 (br. d), 2.70 -2.50 (m), 1.57 (s), 1.55 (s), 1.52 (s), 1.50-1.20 (m), 1.33 (s), 1.27 (t, J=7 Hz), 1.21 (t, J=7 Hz), 1.15-1.10 (m), 0.75-0.65 (m), 0.30-0.20 (m). EXAMPLE A2
Prepared by the procedure described in Example AI, Step B from the intermediate d2 from Example A1, step A (40 mg) and HC1 gas at 0°C in ethyl acetate (3 mL). Product: 28 mg. FAB-MS calc. for C23H32N4O4: 428 ; Found: 429 (M+H) -111 - -111 - LV 11525 iHNMR (400 MHz, CD3OD): compound exists as a mixture of rotamers (about 5:1). 7.56 (d, J= 8 Hz 5/6 H), 7.50 (d, 1/6 H), 7.34 (d, J=8 Hz, 5/6 H), 7.31 (d, 1/6 H), 7.12-7.00 (m, 3 H), 5.28 (dd, 5/6 H), 5.15-5.11 (m, 1/6 H), 5.11-5.07 (m, 1/6 H), 5.02-4.98 (m, 5/6 H), 4.52-4.45 (m), 4.12 5 (q, J=7 Hz), 4.25-4.00 (m), 3.65 (m), 3.30-3.05(m), 2.80-2.70 (m), 2.32- 2.25 (m), 2.02-1.97 (m), 1.75-1.65 (m), 1.57 (s), 1.52 (s), 1.51 (s), 1.40-0.85 (m), 1.22 (t, J= 7 Hz), 0.41-0.30 (m). EXAMPLE A3
Step A:
To a stirred solution of L-proline benzyl ester hydrochloride 25 (155 mg, 0.64 mmole), Intermediate 1 (250 mg, 0.64 mmole), HOBT (1 eq.), and NMM (0.07 mL, 0.64 mmole) in dichloromethane at 0°, was added EDC (246 mg, 1.28 mmole). The reaction mixture was stirred at 0° ovemight, and then partitioned between 3 N HC1 and ethyl acetate. The organic layer was washed with brine and saturated sodium 3 0 bicarbonate and dried and evaporated. MPLC purifīcation eluting with 50% ethyl acetate gavē the intermediate tripeptide benzyl ester( 338 mg, 91.5%). FAB-MS calc. for C32H40N4O6: 576 ; Found: 577 (M+H) 5 - 112-
Step B:
Prepared by the procedure described in Example AI, Step B from the intermediate from the previous step (280 mg) and.HCl gas in ethyl acetate (10 mL) at 0°C . Reaction time: 25 minūtes. Product: 218 mg. FAB-MS calc. for C27H32N4O4: 476 ; Found: 477 (M+H) iHNMR (400 MHz, CD3OD ): 8.20 (d), 7.54 (d, J=7.9 Hz, 1H) 7.34-7.00 (m, 9H), 5.11 (dd, J=4.2 Hz, 16.5 Hz, 2H), 4.99-4.94 (m, 1H), 4.23-4.20 15 (m, 1 H), 3.58-3.53 (m, 1H), 3.31-3.13 (m, 2H), 2.77-2.75 (m, 1H), 1.71- 1.60 (m, 3H) 1.55 (s, 3H), 1.51 (s, 3H), 1.37-1.33 (m, 1H). EXAMPLE A4
Step A: (dP-Pipecolinic acid. benzvl ester A solution of (dl)-pipecolinic acid (25g), p- toluenesulfonic acid (38g), and benzyl alcohol (84g) in toluene (200 mL) was refluxed 30 under azeotropic conditions for one day. The solution was cooled to room temperature and the resulting crystals were collected to give the desired product (52.4 g). The product was vvashed with 3 N NaOH to remove toluenesulfonic acid, and then reacted with HC1 gas in ethyl acetate to convert it to the hydrochloride salt. LV 11525
Prepared by the procedure described in Example A3, Step A from (dl)-pipecolinic acid benzyl ester hydrochloride (3.5 g). Intermediate 1 (5.00 g), HOBt (1.74 g), NMM (1.42 mL) and EDC (3.94 g). Product: 6.32 g FAB-MS calc. for C33H42N4O6: 590 ; Found: 591 (M+H)
Step C:
Prepared by the procedure described in Example AI, Step B from the intermediate from the previous step (250 mg) and HC1 gas in ethyl acetate at 0°C to give the title compound (211 mg) FAB-MS calc. for C28H34N4O4: 490 ; Found: 491 (M+H) EXAMPLE A5
- 114 -
Step A: - 114 -
A suspension of the product from Example A4, step B (5.30 10 g) and 10% palladium on carbon (270 mg) in ethanol (100 mL) was stirred under a hydrogen balloon for 3 hours. The reaction mixture was filtered through celite, evaporated to give the acid (4.48g).
Step B: 15
Od rVr< NHBoc
NHBoc .\CONHEt C=0 O i rr c=o o /N\>C0NHE,
20
Prepared similarly by the procedure described in Example A3, Step A from the acid intermediate from the previous step (200 mg), ethyl amine hydrochloride (27 mg), HOBt (54 mg), NMM (0.07 mL), and EDC (154 mg) to give a mixture of two diastereomers, which were 25 separated by MPLC eluting with ethyl acetate. The isomer which came out of the column first was designated as dl (76 mg), and the isomer vvhich came out second as d2 (165 mg). dl FAB-MS calc. for C28H41N5O5: 527 ; Found: 528 (M+H) d2 FAB-MS calc. for C28H41N5O5: 527 ; Found: 528 (M+H) 30 - 115- - 115- LV 11525
Step C:
Prepared similarly by the procedure described in Example AI, Step B from intermediate from the previous step (dl) (60 mg) and HC1 gas in ethyl acetate (5 mL) at 0°C to give the title compound (38 mg). Reaction time: 20 minūtes. FAB-MS calc. for C23H33N5O3: 427 ; Found: 428 (M+H) *HNMR (400 MHz, CD3OD ): d 7.63 - 7.00 (m, 5 H), 5.33 (t), 5.40 -5.25 (m), 5.11 - 5.09 (m), 4.32 (br. d), 4.16-4.12 (m), 4.00 (md), 3.35 -3.03 (m), 2.96 (q, J = 7 Hz), 2.30 (dt), 2.19 (br. d), 1.95 - 1.40 (m), 1.66 (s), 1.64 (s), 1.40- 1.20 (m), 1.20-1.00 (m), 1.12 (t, J = 7 Hz), 1.03 (t,J = 7 Hz), 0.65 - 0.52 (m), -0.44 - -0.53 (m). EXAMPLE A6
Prepared similarly by the procedure described in Example AI, Step B from intermediate in Example A5 step B (d2) (100 mg) and HC1 gas in ethyl acetate (5 mL) at 0°C to give the title compound (78 30 mg). Reaction time: 20 minūtes. FAB-MS calc. for C23H33N5O3: 427 ; Found: 428 (M+H) 1HNMR (400 MHz, CD3OD ): d 7.54 (d, J = 8 Hz, 1 H), 7.35 (d, J = 8 Hz, 1 H), 7.16 (s, 1 H), 7.13 - 7.00 (m, 2 H), 4.98 (dd, J = 6 Hz, 10 Hz), 4.93 (d, 4 Hz), 3.53 (br. d, J = 12 Hz, 1 H), 3.35 - 3.22 (m), 3.14 - 3.09 (m, 1 H), 2.85 (dt, J = 3, 13 Hz, 1 H), 2.02 (br. d, J = 12 Hz), 1.65 (s, 3 - 116 - Η), 1.61 (s, 3 Η), 1.10 (t, 7 Ηζ, 3 Η), 1.05- 0.92 (m, 2 Η), 0.72- 0.62 (m, 1 Η), -0.25 - -0.30 (m, 1 Η). EXAMPLE Α7
Step Α:
Prepared by the procedure described in Example A3, Step A from L-proline ethyl ester hydrochloride (115 mg, 0.642 mmole), Intermediate 1 (250 mg, 0.642 mmole), HOBT (1 eq.), NMM(0.07 mL, 0.642 mmole), and EDC (246 mg, 1.28 mmole). Product: 330 mg FAB-MS calc. for C27H40N4O6: 514 ; Found: 515 (M+H)
Step B:
Prepared by the procedure described in Example AI, Step B from the intermediate from the previous step (280 mg) and HC1 gas in ethyl acetate (10 mL) at 0°C. Reaction time: 25 minūtes. Product: 220 mg. - 117 - - 117 - LV 11525 FAB-MS calc. for C22H32N4O4: 414; Found: 415 (M+H) iHNMR (400 MHz, CD3OD ): 7.53 (d, J-7.9 Hz, 1H), 7.34 (d, J-8.1 Hz, 1H), 7.14-7.01 (m, 3H), 4.97-4.84 (m, 1H), 4.15-4.06 (m, 3H), 3.60-3.53(m, 1H), 3.31-3.13 (m, 2H), 2.77-2.72 (m, 1H), 1.72-1.59 (m, 3H), 5 1.57 (s, 3H), 1.50 (s, 3H), 1.36-1.27 (m, 1H), 1.23 (t, J=7.1 Hz, 3H). EXAMPLE A8
Step A: 2-Cvano-1 -hvdroxv-4-phenvlpiperidine
To a stirred solution of 4-phenylpiperidine (10 g, 0.062 mole) in methanol (30 mL), was added a solution of sodium tungstate dihydrate (0.82 g, 2.48 mmole) in water (7 mL). With stirring at 0°, hydrogen peroxide (30%, 13.9 mL, 0.136 mole) was added dropwise. After complete addition, the reaction mixture was stirred for an additional 3 hours, and then sodium cyanide (4.56 g, 0.093 mole) was added, followed by 4 N HC1 (22 mL, 0.088 mole). The reaction mixture was stirred ovemight during which time it warmed to room temperature. The solid was collected by filtration through glass sinter funnel, and the solution was neutralized to pH 7 and was extracted with dichloromethane. The organic extract was combined with the solid and dried over MgS04 and evaporated. Flash column purification eluting with 40% ethyl acetate in hexane gavē 2-cyano-l-hydroxy-4-phenylpiperidine(8.6 g). iHNMR (400 MHz, CDCI3 ): 7.35-7.17 (m, 5 H), 6.01 (br. s, 1H), 4.34 (br. s, 1 H), 3.31 (td, J=3, 11 Hz, 1 H), 3.09 (dt, J=11, 3 Hz, 1 H), 2.93-2.86 (m, 1H), 2.20-2.10 (m, 2 H), 1.97-1.80 (m, 2 H). - 118 -
Step B: 2-Cvano-4-phenylpiperidine
To a stirred solution of the intermediate from the previous step (500 mg) in methanol (10 mL) at room temperature, was added T1CI3 (10% solution in 20-30% hydrochloric acid (3 mL). The mixture was stirred for 15 minūtes and was neutralized by addition of 3 N NaOH. The residue were extracted with dichloromethane four times and the organic extracts was combined, dried over MgS04, and evaporated to give 450 mg of 2-cyano 4-phenylpiperidine, which was used without further purification.
Step C:
Follovving the procedūra from Example A3, Step A, using the intermediate from the previous step, afforded two compounds after MPLC purification eluting with 60% ethyl acetate in hexane. The one vvhich came out of the column first was designated as diastereomer 1, and the other one as diastereomer 2. dl: FAB-MS calc. for C32H39N5O4: 557 ; Found: 558 (M+H) d2: FAB-MS calc. for C32H39N5O4: 557 ; Found: 558 (M+H) - 119 - - 119 - LV 11525
Step D:
Following the experimental procedure from Example A1, Step B using products from the previous step and HC1 gas in ethyl acetate at 0°C gavē the desired products. dl: FAB-MS calc. for C27H31N5O2: 457 ; Found: 458 (M+H) d2: FAB-MS calc. for C27H31N5O2:457 ; Found: 458 (M+H) EXAMPLE A9
Step A: 2-Cyano-4-phenylpvridine
To a stirred solution of 4-phenylpyridine N-oxide (25 g, 0.146 mmol) in dichloromethane (200 ml) at room temperature was added trimethylsilyl cyanide (17.4 g), followed by the slow addition of dimethyl carbamyl chloride (16.2 ml) in dichloromethane (50 ml) over a 30 minūte period. The reaction mixture vvas stirred at room temperature for one day, and then to it potassium carbonate solution (10%, 150 ml) vvas added slowly. Stirring continued for an additional 30 minūtes, the - 120- organic layer was separated, and the aqueous layer was extracted with dichloromethane. The extracts were combined and dried over magnesium sulfate. Evaporation in vacuo gavē a crude reaction product (35 g) as a white solid. It was used vvithout further purification. 5 FAB-MS calc. for C12H8N2: 180 ; Found: 181 (M+H) 1HNMR (400 MHz, CD30D): 8.71 (dd, 1 H), 8.19 (dd, 1H), 7.94 (dd, 1 H), 7.81 -7.78 (m, 2 H), 7.56-7.50 (m, 3 H).
Step B: 4-Phenvlpvridine-2-carboxvlic acid 10 A solution of the product from the previous step (25 g) in 100 ml of 6N HC1 was refluxed for one day. The solution was cooled to room temperature, at which time, crystallization started to occur. The crystals were filtered and collected to give the product (27.5 g, 87%). 15 Step C; Ethvl 4-phenvlpvridine-2-carboxvlate hvdrochloride
To a solution of the intermediate prepared in the previous step (5.0 g, 21.2 mmol), ethanol (2 g), DMAP (20 mg) and N-methyl morpholine (1 eq.) in dichloromethane, was added EDC (1.5 eq.). The reaction mixture was stirred at 0°C ovemight. The solution \vas washed 20 with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate; then filtered and concentrated. Purification by MPLC eluting with 40% ethyl acetate in hexane gavē ethyl 4-phenylpyridine-2- carboxylate (3.71 g, 77%). The compound was converted to its HC1 salt by treatment with HC1 gas in ethyl acetate followed by evaporation. 25
Step D: Ethvl 4-phenylpiperidine-2-carboxvlate A suspension of the product from the previous step (200 mg) and platinum dioxide (20 mg) in ethanol was stirred under a hydrogen balloon for three hours. The reaction mixture was then filtered through 30 celite and evaporated. The resulting material was used without further purification. - 121 - LV 11525
Step E:
To a solution of the intermediate prepared in the previous step (200 mg ), and Intermediate 1 (1 eq.), HOBT (1 eq.), and NMM (1 eq.) in dichloromethane was added EDC (1.5 eq.) at 0°C. The reaction mixture was stirred at 0°C ovemight. The solution was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and then concentrated. Purification by MPLC eluting with 50% ethyl acetate in hexane provided the compound as a diastereomeric mixture.
Step F:
To a stirred solution of the intermediate from the previous step (30 mg) in ethyl acetate (2 mL) at 0°C, was bubbled HC1 gas until it was saturated. The reaction mixture was stirred for 15 minūtes and was evaporated to dryness to give the product. FAB-MS calc. for C29H36N4O4: 504; Found 505 (M+H) - 122 -
The additional Products shown in Table AI were prepared according to Example A9 Steps E and F, using Intermediate 2 or Intermediate 3 and the intermediate from step D.
TABLE AI: ADDITIONAL EXAMPLES
O C02Et
Product entry Rl MF FAB-MS (M+l) 1 Ph(CH2)3- C29H39N3O4 494 2 PhCH20CH2- C28H37N3O5 496
Likewise the compounds shown below are prepared according to Example A9 by introduction of the 2-cyano substitutent to a variety of readily available substituted 4-phenylpyridines with separation of isomers where necessary, follovved by hydrolysis, reestrification with anhydrous acidic ethanol and hydrogenation of the pyridine ring to prepare the following intermediates: - 123 - LV 11525
which may be reacted with Intermediate 1 or 3 to give the following compounds respectively.
- 124-
EXAMPLE A10
A solution of 3-benzylpyridine (25 g, 0.148 mol) in hydrogen peroxide (30%, 15.1 mL) and acetic acid (100 mL) was refluxed for one day. Then more hydrogen peroxide (3 mL) was added and the resulting mixture was refluxed ovemight. The reaction mixture was then evaporated and partitioned between a mixture of 3 N HC1, brine and dichloromethane. The organic layer was separated, dried and evaporated to give the desired compound (27.6 g, 100%). -125- -125- LV 11525
Step B: 3-Benzvl-2-cvanopvridine
Prepared according to the procedure in Example A9 step A from the intermediate from the previous step (27 g). The crude reaction product was purified by a Si02 flash column eluting with 20-40% ethyl 5 acetate in hexane to give 5-benzyl-2-cyanopyridine (3.0g, 10%) and 3-benzyl-2-cyanopyridine (24.2 g, 85%).
Step C: 3-Benzvlpvridine-2-carboxvlic acid hvdrochloride A solution of 3-benzyl-2-cyanopyridine (19.1 g) in 10 concentrated hydrochloric acid (50 mL) and water (50 mL) was refluxed for two days. The resulting solution was evaporated to give a solid (30. lg 100%, which contains an equal molar amount of ammonium chloride). 15 Step D: Ethvl 3-benzvlpvridine-2-carboxvlate hvdrochloride
Thionyl chloride (15.2 g) was carefully dissolved in ethanol (300 mL) and the resulting solution was added to the intermediate from the previous step (20 g). The mixture was refluxed ovemight and then evaporated to give the crude product as hydrochloride salt. The crude ο n product was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic solution was dried, evaporated and purified with a short Si02 column to give the product as free base (18.2 g). To a solution of this intermediate (16.5 g) in ethyl acetate (80 mL), was bubbled HC1 gas.until it was saturated. The mixture was then 25 evaporated to give the HCļ salt (18.9 g).
Step E: Ethvl 3-benzvlpiperidine-2-carboxvlate hvdrochloride A suspension of the product from the previous step (1.0 g) and platinum dioxide (100 mg) in ethanol was stirred under a hydrogen 30 balloon for five hours. The reaction mixture was then filtered through celite and evaporated to give the desired compound. - 126 -
Step F:
To a solution of the intermediate prepared in the previous step (180 mg, 0.634 mmol), and Intermediate 1 (1 eq.), HOBT (1 eq.) and ίο NMM (1 eq.) in dichloromethane, was added EDC (1.5 eq.) at 0°C. The reaction mixture was stirred at 0°C ovemight. The solution was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate; then filtered and concentrated. Purification by MPLC eluting with 50% ethyl acetate in hexane provided two enantiomerically pure compounds. 15 The compound which came out first from the column was designated as dl (146 mg); and the compound which came out of the column second was designated as d2 (141 g). dl FAB-MS calc. for C35H46N4O6: 618; Found 619 (M+H) d2 FAB-MS calc. for C35H46N4O6: 618; Found 619 (M+H) 20
Step G:
To a stirred solution of the intermediate dl from the 30 previous step (130 mg) in ethyl acetate (2 mL) at 0°C, was bubbled HC1 gas until it was saturated. The reaction mixture was stirred for 15 minūtes and it was evaporated to dryness to give the product (111 mg, 95%) FAB-MS calc. for C30H38N4O4: 518; Found 519 (M+H) - 127- LV 11525
Step H:
The compound was prepared according to the procedure of 10 the previous step from the intermediate d2 from Step F (130 mg). Product: 114 mg, 98% FAB-MS calc. for C30H38N4O4: 518; Found 519 (M+H) 15
The additional products shown in Table Ali were prepared according to Example A10 Steps F and G, using Intermediate 2 or Intermediate 3 and the intermediate from step E. No separation of the diastereoisomers was observed during MPLC purifīcation of the Boc precursor.
TABLE Ali: ADDITIONAL EXAMPLES 20 25
C=0 A O C02Et cis
Bn Product entry Ri MF FAB-MS (M+l) 1 Ph(CH2)3- C30H4IN3O4 508 2 PhCH20CH2- C29H39N3O5 510 - 128- EXAMPLE Ali
Step A: Diethvl piperidine-2.3-(cisVdicarboxvlate 10 Hydrogen chloride gas was bubbled into ethanol (400 mL) until 22 g was absorbed. Pyridine-2,3-dicarboxylic acid (100 g) was dissolved in this solution and the resulting mixture was refluxed ovemight. The reaction mixture was divided into two portions and each was shaken with Pt02 (1.4 g) in Parr shakers under 40 psi of hvdrogen 15 for 8 hours. The reaction mixture was combined and filtered through celite and washed with plenty of ethanol. Evaporation gavē a gray solid which was vvashed with ethyl acetate to give a white solid after fīltration (74.8 g) 20 Step B:
The compound was prepared according to the procedure of Example AI Step A from the intermediate from the previous step (178 mg) and Intermediate 1. Product: 234 mg FAB-MS calc. for 30 C31H44N4O8: 600 ; Found 601(M+H) - 129- - 129- LV 11525
Sted C:
The compound was prepared according to the procedure of Example AI Step B from the intermediate from the previous step (230 10 mg). Product: 215 mg FAB-MS calc. for C26H36N4O6: 500 ; Found 501(M+H), 523 (M+Na)
The additional intermediates shovvn in Table Aili were prepared from the corresponding pyridine analogs according to the above 15 established procedures from the corresponding pyridine derivatives as exemplified in Example Ali step A and the final products were prepared according to Steps B and C
TABLE Aili: ADDITIONAL EXAMPLES
Product
Intermediate (OH) Product entry MF MF FAB-MS (M+l) FAB-MS (M+l) 1 H /N Ch3 C24H34N4O4 443 diastereomeric mixture - 130 - 2 H 1 /N^CH3 C25H36N404 457 ļp'"* C02Et ch3 diastereomeric mixture 3a H N^CH3 C25H36N4O4 457 '"COsEt ch3 diastereomeric mixture a:The intermediate was prepared by epimerization of its ali cis isomer with KHMDS in THF.
Step A: Diethvl N-Boc-piperidine-(cis)-2.3-dicarboxvlate
To a stirred solution of the intermediate from Example AI 1 Step A (10 g, 37.6 mmol) and triethylamine (6.4 mL) in dichloromethane (50 mL), was added di-t-butyl dicarbonate (10.7 g) and the resulting mixture was stirred at room temperature ovemight. The reaction mixture was diluted with dichloromethane and was washed with a mixture of 3 N HCI and brine. The organic layer was dried, evaporated and purified with a silica gel column eluting with a gradient of 10-30% ethyl acetate in hexane to give the desired compound (9.61 g).
Step B:
Boc C02Et N C02Et Bn EXAMPLE A12
- 131 - LV 11525
To a stirred solution of KHMDS (3.79, 19 mmol) in THF (150 mL) at -78°C under argon was added a solution of diethyl N-Boc-piperidine-(cis)-2,3-dicarboxylate (5 g, 15.2 mmol) over a 30 minūte period. The solution was allowed to stir an additional 30 minūtes at -78°C; then benzyl bromide (2.73 g, 15.9 mmol) was added slowly to the solution. The reaction mixture was stirred ovemight and allovved to warm to room temperature. The material was concentrated, then diluted vvith water, and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography, eluting with 20% ethyl acetate in hexane provided two diastereoisomers. The compound which came out first from the column was designated as dl (1.01 g); and the compound which came out of the column second was designated as d2 (3.75 g). NMR established the esters are trans in dl and cis in d2-
Step C:
H HCI NL .C02Et r, C02Et Bn *
The compounds were prepared according to the procedure of Example AI Step B from the intermediates from the previous step. Intermediate dl (850 mg) yielded the dl title compound (711 mg, 98%). Intermediate d2 (3.2 g) yielded the d2 title compound (2.58 g, 96%) dl FAB-MS calc. for C18H25NO4: 319 ; Found 320(M+H) d2 FAB-MS calc. for CI8H25NO4: 319 ; Found 320(M+H)
Step D:
- 132 -
The compounds were prepared according to the procedure of Example AI Step A from the intermediates from the previous step. Intermediate dl (228 mg) yielded a mixture of trans diastereomers (128 mg, 30%).
Intermediate d2 (228 mg) yielded a mixture of cis diastereomers (164 mg, 30%).
Step E:
The compounds were prepared according to the procedure of Example AI Step B from the intermediates from the previous step. Intermediate dl (120 mg) yielded the title compound as mixture of trans (dl) diastereomers (106 mg, 97%).
Intermediate d2 (155 mg) yielded the title compound as mixture of cis (d2) diastereomers (135 mg, 96%). dl FAB-MS calc. for C33H42N4O6: 590 ; Found 591(M+H) d2 FAB-MS calc. for C33H42N4O6: 590 ; Found 591(M+H)
The additional intermediates shown in Table AIV were prepared according to the above established procedures using N-Boc intermediates from Table Aili as exemplified in Example A12 Steps A, B and C and the final products were prepared according to Steps D and E. LV 11525
Product
Intermediate (OH) Product entry MF MF FAB-MS (M+l) FAB-MS (M+l) H i ,N CH3 ^^C02Et Bn ^
H .N. .CH3 C02Et dl: C31H40N4O4 533
Bn dl: C31H40N4O4 533
H
mixture of diastereomers C32H42N4O4 547
Likewise the compounds shown below are prepared according to Example A12 by alkylating with 2-picolyl chloride or 4-bromomethylthiazole to give the following intermediates:
- 134 - 15 20 25 which may then be reacted with Intermediates 1 or 2 to give the following compounds respectively:
EXAMPLE A13
30 - 135 - - 135 - LV 11525
Step A:
To a stirred solution of dl-2-pipecolamidoethanol (100 mg, (1.16 mmol), HOBT (78.38 mg, 1.16 mmol) and Intermediate 1 (226.12 mg, 1.16 mmol) in dichloromethane (3ml) at ambient temperature was added 4-methyl morpholine (63.8 ml, (1.16 mmol). The mixture was cooled to 0° C and to which was added EDC (222.3 mg, 2.32 mmol). The reaction mixture was stirred at room temperature for 16 h. After evaporation, the residue was partitioned in ethyl acetate and 1N hydrochloric acid. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to an oily foam which was purified by preparative tic (acetone/chloroform: 3/7) to give 91 mg of the product (Rf= 0.45). CI-MS : calc. for C28H41N5O6: 543 ; Found 544(M+H) lH NMR (400 MHz, CDCI3): δ 8.35 (br.s, 1H), 7.57 & 7.55 (2s, 1H),7.35, 7.33, (2s, 2H), 7.17 (t, J= 6.95Hz, 1H), 7.15-7.07 (m, 3H), 7.03 (distorted t, J= 4.95 Hz, 1H), 5.16 (d, J=4.68 Hz, 1H), 4.94 (m, 2H), 3.65 (m, 2H), 3.55-3.10 (m, 5H), 2.9-2.62 (m, 4H), 2.3-2.2 (m, 1H), 1.43,1.46 and 1.41 (3 s, total 15H), 1.00 (m, 1H), 0.83 (m, 1H).
Step B:
-136 -
Prepared according to the experimental procedure from Example AI Step B using product from the previous step and HC1 gas in ethyl acetate at 0°C. CI-MS : calc. for C23H33N5O4: 443 ; Found 444(M+H) 5 lH NMR (400 MHz, CD3OD): d δ 7.54 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.1
Hz), 7.12 (distorted t, J=7.5 Hz, 1H), 7.03 (distorted t, J=7.5Hz, 1H), 4.97-4.92 (m, 1H), 3.63 (m, 1H), 3.75 (br. d, 1H), 2.82 (br. t, J=2.3 Hz, 1H), 2.07 (br. d, J=2.3 Hz, 1H), 1.66-1.57 (m, 6H), 1.55-0.88 (m, 4H), 0.70-0.55 (m, 1H). 10
The additional compounds shown in Table AV were prepared according to Steps A and B using Intermediate 1. The piperidine intermediates were either commercially available or were prepared according to the above established procedures or from literature 15 procedures.
TABLE AV: ADDITIONAL EXAMPLES
25 W MF FAB(or CI)-MS (M+l) 1 -CO2CH3 C22H30N4O4 415 2 -CONH(CH2)20H C23H33N5O4 444 3 -CONHCH2C(CH3)20H C25H37N5O4 472 30 4 -CONHCH2CH(OH)CH3 C24H35N5O4 458 5 -CO2NH2 C21H29N5O3 399 (EI, M+) 6 -CH2COCH3 C23H32N3O4 413 7 -CH(OH)Ph-/?-Cl C27H33N4O3CI 497 8 -CH(OH)CH2CH3 C23H34N4O3 415 - 137 - LV 11525
9 -CONHBn C28H35N5O3 490 10 -CONH(CH2)2CH3 C24H35N5O3 442 11 H -CH2^'N'ļ^ C25H37N5O3 456 12 -CONHPh C27H33N5O3 476 13 N-N C21H28N8O2 425 H 14 ch3 C23H30N6O3 439 N“Y
The additional compounds shown in Table AVa were prepared according to Steps A and B using Intermediate 3 and some of intermediates used in the previous table.
TABLE AVa: ADDITIONAL EXAMPLES
Product W MF FAB(or CI) (M+l) 1 -CO2CH2CH3 C23H35N3O4 418 2 -CONHCH2C(CH3)20H C25H40N4O4 461 3 -CONH(CH3)2 C23H33N5O3 428 4 -CH(OH)Ph-/?-Cl C27H36N3O3CI 486 -138- 15
Step A: EXAMPLE Β1
To 7.0 g of 2-bromobenzyl alcohol in 7.0 g of dihydropyran at rooin temperature was added 2 drops of concentrated hydrochloric acid and stirred at room temperature for lh. The reaction mixture was diluted with 150 mL of ether and washed with saturated NaHC03 (2X100 mL), brine (150 mL), dried over MgS04 and concentrated to give a thick oily material. The residue was purified by flash chromatography with hexane-EtOAc as eluent to give 10 g of the tetrahydropyranyl ether.
To 260 mL of dry ether at -78°C was added 23.6 mL of 1.6 M solution of nBuLi in hexanes. To this solution was added a solution of 7.5 g of the THP compound in 100 mL of ether and stirred at -78°C for 30 min. and -40°C for an additional 30 min. This solution was added in a dropvvise manner to a mixture of 2.16 g of pyridine and 6.3 mL of t-butyldimethyl-silyl triflate in 200 mL of ether at -78°C. The reaction mixture was allowed to warm up to room temperature and stirred ovemight. The reaction was quenched with 75 mL of water and oxygen - 139 - LV 11525 gas was bubbled in for 3h. The reaction mixture was diluted with ether and 3N HC1 till the pH = 1 and then the organic layer was separated. The aqueous layer was basified with 20% NaOH till the pH = 8-9 and then extracted with chloroform (3X100 mL). The organic layer was washed 5 with water, brine (200 mL), dried over Na2S04, filtered, and evaporated.
To 3.42 g of the above compound in 100 mL of CHC13 was added 30 g of activated manganese dioxide and stirred ovemight. The solids were filtered off through a pad of celite, and the fīltrate was evaporated.
10 To 2.4 mL of triethylphosphonoacetate in 30 mL of dry THF at 0°C was added 16.3 mL of a solution of sodium hexamethyldisilazide in THF and stirred for 30 min. A solution of the above aldehyde intermediate in 10 mL of THF was added and stirred for 30 min. The reaction was quenched with 25 mL of saturated NH4CI solution, and 15 extracted with EtOAc(3X25 mL). The combined organics were washed with brine, dried over Na2S04, and concentrated. Flash chromatography of the residue with hexane-EtOAc (4:1) as eluent gavē 1.5 g of the desired product as a pale yellow solid. lH NMR (CDCI3, 400MHz) d 8.63 (d, 2H), 7.68 (dd, 1H), 7.60 (d, 1H), 20 7.45-7.35 (m, 2H), 7.30 (dd, 1H), 7.35 (d, 1H), 4.15 (q, 2H), 1.23 (t, 3H).
Step B: 25
HHCI
To 1.5 g of the above intermediate in 25 mL of methanol was added 5 mL of 4M HC1 in EtOAc and evaporated to dryness. This solid was dissolved in 30 mL of methanol and 0.50 g of Pt02 was added and hydrogenated at 50 psi for 5h. The catalyst was filtered off through a pad of celite and the fīltrate was concentrated to give the title compound. 30 - 140- 1η NMR indicated that this material contained about 5% of the cyclohexyl-piperidine. lH NMR (CD3OD, 400MHz) d 7.40-7.20 (m, 4H), 4.08 (q, 2H), 3.50 (m, 2H), 3.25-3.10 (m, 3H), 3.00 (t, 2H), 2.60 (t, 2H), 2.03-1.90 (m, 4H), 1.20 (t, 3H).
Step C:
To a mixture of the above intermediate in 30 mL of CH2CI2 \vas added 0.82 mL of triethylamine, 1.2 mL of NMM, 0.90 g of HOBT, 2.13 g of (2R)-N-tBOC-5-phenylpentanoic acid (prepared as described in Η. K. Chenault et al. J. Am. Chem. Soc., 111, 6354-6364 (1989)), and fmally 1.7 g of EDC and stirred at room temperature for 18h. The reaction mixture was poured into a saturated NaHC03 solution and extracted with CH2CI2· The combined organics were washed with 0.1N HC1, brine, dried over Na2S04, and concentrated.
The above crude material was dissolved in 30 mL of CH2CI2 and 10 mL of TFA was added and stirred at RT for lh. The solvent was evaporated to dryness and the residue was neutralized with aqueous Na2C03 solution, and extracted with CH2CI2. The combined organics were washed with brine, dried over K2CO3, and concentrated. To a mixture of this intermediate in 30 mL of CH2CI2 was added 1.04 g of HOBT, 1.56 g of N-tBOC-a-methylalanine, and finally 1.8 g of EDC and stirred at room temperature for 4h. The reaction mixture was poured in saturated NaHC03 solution and extracted with CH2CI2. The - 141 - LV 11525 combined organics were washed with 0.1N HC1, brine, dried over MgS04, and concentrated. Flash chromatography of the oily residue with CH2Cl2-acetone-ether (6:1:1) as eluent gavē the desired material. lH NMR (CDCI3,400MHz) d 7.30-6.98 (m, 9H), 5.00-4.85 (m, 2H), 5 4.72-4.64 (m, 1H), 4.13 (2q, 2H), 4.00-3.82 (m, 1H), 3.14-2.85 (m, 4H), 2.7-2.50 (m, 5H), 1.83-1.50 (m, 5H), 1.50 (s, 3H), 1.46 (s, 1.5H), 1.44 (s, 1.5H), 1.40 (s, 9H), 1.40-1.28 (m, 1H), 1.23 (2t, 3H).
Step D: 10
20 25
To 1.70 g of the intermediate in Step C in 30 mL of CH2CI2 was added 10 mL of TFA and stirred at RT for lh. The reaction was evaporated to dryness, basified with aqueous Na2C03, and extracted vvith CH2CI2. The combined organics were washed with brine, dried over K2CO3, fīltered, and evaporated to give free base as a thick oil.
This material was dissolved in 5 mL of ether at 0°C and 0.50 mL of 4M HC1 in EtOAc was added. The precipitate was fīltered under an N2 atmosphere and dried to give the title compound. lH NMR (CD3OD, 400MHz) d 7.30-6.98 (m, 9H), 5.00-4.85 (m, 2H), 4.72-4.64 (m, 1H), 4.13 (2q, 2H), 4.00-3.82 (m, 1H), 3.14-2.85 (m, 4H), 2.7-2.50 (m, 5H), 1.83-1.50 (m, 5H), 1.50 (s, 3H), 1.46 (s, 1.5H), 1.44 (s, 1.5H), 1.40-1.28 (m, 1H), 1.23 (2t, 3H). 30 - 142- EXAMPLE B2
Step A:
To a solution of 0.20 g of the intermediate from Example Bl, Step C in 5 mL of anhydrous THF was added 46 mg of potassium trimethylsilanoate. After 2h an additional 46 mg of potassium trimethylsilanoate and 2 mL of THF were added and stirred at RT ovemight. The reaction was diluted with 10 ml of water and washed with ether (2X10 mL). The aqueous layer was acidified with 0.1N HC1 to pH=2 and extracted with CH2C12 (2X15 mL). The combined organics were vvashed with brine, dried over Na2S04, filtered and concentrated. Flash chromatography of the residue with CHCl3-Me0H-NH40H (85:15:1) as the eluent gavē 56 mg of the desired material. - 143- LV 11525 lH NMR (CDCI3,400MHz) d 7.32-7.20 (m, 4H), 7.20-6.98 (m, 5H), 5.10 (bs, 1H), 5.00-4.90 (m, 1H), 4.65 (bt, 1H), 4.90 (dd, 1H), 3.10-2,85 (m, 4H), 2.70-2.50 (m, 5H), 1.80-1.50 (m, 5H), 1.50 (s, 4H), 1.46 (s, 1H), 1.42 (s, 1H), 1.38 (s, 9H), 1.35-1.20 (m, 1H).
Step B:
To the above intermediate at RT was added 2 mL of 4M HC1 in EtOAc maintained at RT for 2h. The reaction was evaporated to 20 dryness and the residue was triturated with ether to give the title compound as a white solid. ]H NMR (CD3OD, 400MHz) d 8.15 (t, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.60 (bd, 1H), 4.05 (d, 1/2H), 3.95 (d, 1/2H), 3.25-3.05 (m, 2H), 3.00 (dt. 2H), 2.80-2.50 (m, 5H), 1.85-1.63 (m, 6H), 1.63 (s, 2H), 1.60 (s, 25 4H), 1.60-1.20 (m,2H). 30 - 144- EXAMPLE B3
The title compound was prepared as described in Example B1 Steps C and D, but commercially available N-t-B0C-0-benzyl-D-ļ5 serine was substituted for (R)-2-N-t-BOC-5-phenylpentanoic acid. lH NMR (CD3OD, 400MHz) d 8.30 (d, 1/2H), 8.23 (d, 1/2H), 7.40-7.25 (m, 5H), 7.20-7.05 (m, 3.5H), 6.88 (d, 1/2H), 5.20 (m, 1H), 4.70-4.50 (m, 3H), 4.20-4.05 (m, 3H), 3.84-3.65 (m, 2H), 3.28-2.95 9m, 4H), 2.75 (q, 1H), 2.58 (dt, 2H), 1.85-1.70 (m, 2H), 1.64 (s, 2H), 1.61 (s, 4H), 1.55-20 1.40 (m,2H), 1.20 (2t, 3H). EXAMPLE B4
To 54 mg of the compound prepared in Example B3 was added 2 mL of 2N aqueous HC1 and stirred at RT ovemight. The solvents were removed under reduced pressure and the residue was dried under vacuum to give the title compound. - 145- LV 11525 lH NMR (CD3OD, 400MHz) d 8.30 (d, 1/2H), 8.23 (d, 1/2H), 7.40-7.25 (m, 5H), 7.20-7.05 (m, 3.5H), 6.88 (d, 1/2H), 5.20 (m, 1H), 4.70-4.50 (m, 3H), 4.20-4.05 (m, 1H), 3.84-3.65 (m, 2H), 3.28-2.95 (m, 4H), 2.75 (q, 1H), 2.58 (dt, 2H), 1.85-1.70 (m, 2H), 1.64 (s, 2H), 1.61 (s, 4H), 1.55-1.40 (m, 2H). EXAMPLE B5
To a solution of 0.109 g of the intermediate obtained in Step 20 A Example B2 in 3 mL of CH2CI2 was added 0.017 mL of ethanolamine, 34 mg of HOBT, and 58 mg of EDC and stirred at RT ovemight. The reaction mixture was diluted with 10 mL of CH2CI2 and washed with 5 mL of 0.10N HC1, 5 mL of saturated aqueous NaHC03, dried over MgSC>4, and concentrated. Flash chromatograhy of the residue with 25 CH2Cl2-acetone (3:2) as the eluent gavē the coupled product.
As before, the above material was treated with CH2CI2-TFA at RT for 30 min., evaporated to dryness, and triturated with ether to give the title compound as a pale yellow solid. lH NMR (CD3OD, 400MHz) d 8.15 (t, 1H), 7.30-7.00 (m, 9H), 4.95 (m, 1H), 4.60 (bd, 1H), 4.40 (bs, 1H), 4.00 (bdd, 1H), 3.60-3.50 (m, 2H), 3.40-3.10 (m, 4H), 3.05-2.90 (m, 2H), 2.85-2.60 (m, 5H), 2.52-2.40 (m, 4H), 1.90-1.65 (m, 6H), 1.63 (s, 2H), 1.60 (s, 4H), 1.60-1.20 (m, 2H). 30 - 146- EXAMPLE B6
To 9.0 g of 2-bromophenethyl alcohol in 6.12 mL of dihydropyran at room temperature was added 2 drops of concentrated hydrochloric acid and stirred at room temperature for lh. The reaction mixture was diluted with 150 mL of ether and washed with saturated NaHC03 (2X100 mL), brine (150 mL), dried over MgS04 and concentrated to give a thick oily material. The residue was purified by flash chromatography with hexane-EtOAc as eluent to give 10 g of the ether.
To 200 mL of dry ether at -78°C was added 17.7 mL of 1.6 M solution of nBuLi in hexanes. To this solution was added a solution of 8.0 g of the ether intermediate in 100 mL of tetrahydropyranyl ether and stirred at -78°C for 30 min. and -40°C for an additional 30 min. This solution was added in dropwise manner to a mixture of 2.16 g of pyridine and 6.3 mL of t-butyldimethylsilyl triflate in 200 mL of ether at -78°C. - 147- LV 11525
The reaction mixture was allowed to warm up to room temperature and stirred ovemight. The reaction was quenched with 75 mL of water and oxygen gas was bubbled in for 3h. The reaction mixture was diluted with ether and 3N HC1 till the pH = 1 and then the organic layer was separated. The aqueous layer was basified with 20% NaOH till the pH = 8-9 and then extracted with chloroform (3X100 mL). The organic layer was washed with water, brine (200 mL), dried over Na2S04, filtered, and evaporated. Flash chromatography of the residue with hexane-ethylacetate (1:1) as the eluent gavē the desired product.
Approximately 0.90 g of the phenyl-pyridine intermediate prepared as described above was converted to the hydrochloride salt by treating it with 4M HC1 in EtOAc. *H NMR (CDCI3, 400MHz) d 8.90 (d, 2H), 8.20 (dd, 1H), 7.73-7.35 (m, 4H), 3.70 (t, 2H), 2.83 (t, 2H).
Step B:
To 0.90 g of the above intermediate in 25 mL of methanol was added 0.10 g of Pt02 and hydrogenated with pressurized hydrogen at 50 psi for 5h. The catalyst was filtered off and the filtrate was concentrated. The residue was treated with 1.4 g of di-t-butylcarbonate in 3 mL of dioxane, 1 mL of vvater, and 1 mL of triethylamine for 18h. The protected piperidine was separated by flash chromatography with CH2Cl2-acetone (10:1) as the eluent. -148 - Το 0.25 g of protected piperidine intermediate synthesized above was added 2 mL of CH2CI2 and 0.50 mL of TFA and stirred at RT for 30 min. The reaction was evaporated to dryness and azeotroped with toluene.
To a solution of the above residue in 2 mL of CH2CI2 was added 0.079 g of HOBT, 0.14 g of Intermediate 2,0.070 mL of NMM, and 0.090 g of EDC and stirred at RT ovemight. The reaction mixture was poured into saturated NaHCC>3 and extracted with CH2CI2. The combined organics were washed with 0.5N HC1, brine, dried over MgS04, and concentrated. Flash chromatography of the residue with CH2Cl2-acetone (9:1) as the eluent gavē the coupled product.
Deprotection of the N-t-butoxycarbonyl group was carried out by treating the above intermediate with 1 mL of TFA in 2 mL of CH2CI2 for 2h. Concentration of the reaction mixture, trituration with ether and drying under vacuum gavē the title compound as a colorless solid. lH NMR (CD3OD, 400MHz) d 7.40-6.88 (m, 9H), 5.17 (bs, 1H), 4.77-4.50 (m, 3H), 4.18 (bd, 1H), 3.80-3.65 (m, 4H), 3.30-3.05 (m, 4H), 2.95-2.70 (m, 2H), 1.85-1.60 (m, 2H), 1.60 (s, 2H), 1.58 (s, 4H), 1.70-1.45 (m, 2H). EXAMPLE B7
Step A: - 149 - LV 11525
BOC
10 prepared in Step A, Example B1 was attempted in different solvents like ethanol and methanol in the presence and absence of conc. HC1. Transesterification as well as unselective reduction of the pyridine was observed. Several of these reactions were combined and treated with excess di-t-butylcarbonate in CH2CI2 and triethylamine. Approximately 15 5.0 g of the crude material thereby obtained after acid work-up was treated with 1.6 g of NaOH in 100 mL of methanol and 10 mL of water for 2h. The reaction mixture was diluted with water and vvashed with ether. The aqueous layer was acidified with 0.50N HC1 till acidic and extracted with CHCI3. The combined organics were washed with brine, 20 dried over Na2S04, filtered, and concentrated. To about 4.0 g of this piperidine acid in 150 mL of CH2CI2 at RT was added 1.86 mL of benzyl alcohol, 1.90 g of HOBT, 3.45 g of EDC and a catalytic amount of DMAP, and stirred at RT ovemight. The reaction mixture was vvashed vvith saturated NaHC03, 0.50N HC1, brine, dried over Na2S04, filtered 25 and concentrated. The desired material was obtained after purification via flash chromatography. lH NMR (CDCI3,400MHz) d 7.40-7.28 (m, 5H), 7.22-7.10 (m, 4H), 5.12 (s, 2H), 4.25 (bs, 2H), 3.04 (t, 2H), 2.94-2.70 (m, 3H), 2.67 9t, 2H), 1.75-1.60 (m, 3H), 1.53 (s, 9H), 1.33-1.20 (m, 1H). 30 -150-
Step B:
To a solution of 0.70 g of the above intermediate in 2.5 mL of CH2CI2 was added 1 mL of TFA and the reaction mixture was stirred at RT for lh. The reaction mixture was evaporated to dryness, dissolved in saturated aqueous NaHC03, and extracted with CH2CI2. The combined organics were washed with brine, dried over K2CO3, and concentrated. The residue was reacted with Intermediate 1 as described in Step B, Example B6. Flash chromatography of the residue with hexane-acetone-ether (6:1:1) as the eluent gavē 0.47 g of the desired material.
Step C:
To a solution of 0.20 g of the above intermediate in EtOAc at 0°C was bubbled in HC1 gas for about 10 seconds. The reaction mixture was capped and stirred for 30 min. Ether was added and the - 151 - LV 11525 precipitate was filtered under an N2 atmosphere. This gavē 0.195 g of the title compound as a white solid.
The NMR indicated a 2:1 mixture of rotamers. NMR (CD3OD, 400MHz) d 8.30 and 8.20 (2d, 1H), 7.53 and 7.45 (2d, 1H), 5 7.40 and 7.35 (2d, 1H), 7.30-7.00 (m, 11 andl/3), 6.54 (d, 2/3H), 5.30- 5.18 (m, 1H), 5.09 and 5.05 (2s, 2H), 4.60 and 4.55 (2d, 1H), 3.90 (2d, 1H), 3.35 (dd, 1H), 3.20 (dd, 1H), 3.00-2.85 (m, 3H), 2.75-2.40 (4H), 1.64 (s, 6H), 1.40 (d, 2/3H), 1.06 (d, 2/3H), 0.73 (dt, 1/3H), -0.03 (dt, 1/3H). 10 EXAMPLE B8
To a solution of 0.19 g of the intermediate ffom Step C, Example B7 in 3 mL of dioxane was added 50 mg of 10% Pd/C and 25 hydrogenated under H2 balloon for 3h. The reaction was slow so about 50 mg of 20% Pd(OH)2/C was added and hydrogenated ovemight. The catalyst was filtered off through a pad of celite and washed with dioxane. Evaporation of the filtrate gavē the title compound as a pink solid.
The NMR indicated a 2:1 mixture of rotamers. NMR 30 (CD3OD, 400MHz) d 8.30 and 8.20 (2d, 1H), 7.53 and 7.45 (2d, 1H), 7.40 and 7.35 (2d, 1H), 7.20-7.00 (m, 6 and 1/3), 6.54 (d, 2/3H), 5.30-5.18 (m, 1H), 4.60 and 4.55 (2d, 1H), 3.90 (2d, 1H), 3.35 (dd, 1H), 3.20 (dd, 1H), 3.00-2.85 (m, 3H), 2.75-2.40 (4H), 1.64 (s, 6H), 1.40 (d, 2/3H), 1.06 (d, 2/3H), 0.73 (dt, 1/3H), -0.03 (dt, 1/3H). - 152- ΕΧΑΜΡΤΕ Β9
Το 0.20 g of the benzyl alcohol-pyridine intermediate synthesized in Step A of Example B1 was added 2 mL of dry acetone and 0.10 mL of benzyl bromide and stirred at room temperature for lh. The volatiles were removed on the rotary evaporator and the residue was azeotroped with toluene. The residue was dissolved in methanol and treated with 0.10 g of sodium borohydride for lh. The reaction mixture was diluted with water and extracted with CH2C12- The combined organics were washed with brine, dried over magnesium sulfate, filtered, and evaporated. This gavē a mixture of N-benzyl-tetrahydropyridines. which was hydrogenated in ethanol for 5h with 10% Pd/C as the catalyst. The catalyst was filtered off and the filtrate was concentrated. Purification of the residue with CH2Cl2-methanol (90:10) as the eluent gavē 70 mg of a mixture of tetrahydro- and hexahydropyridines. To a solution of 70 mg of the above mixture in 5 mL of CH2CI2 was added 0.10 g of Intermediate 2,0.040 g of HOBT and 0.070 g of EDC and stirred at RT ovemight. The reaction mixture was poured into saturated aqueous NaHC03 and extracted with CH2CI2. The combined organics were washed with brine, dried over Na2S04, and concentrated. Purification of the residue by flash chromatography with hexane-EtOAc (4:1) as the eluent gavē 0.090 g of the coupled product as a mixture of diastereomers.
The above coupled product was hydrogenated in ethanol with 10% Pd/C as the catalyst for 18h. The catalyst was filtered off -153 - LV 11525 through a pad of celite and the filtrate was concentrated. Flash chromatography of the residue with CH2Cl2-ether (6:1) as the eluent gavē 90 mg of the desired product. A fmal deprotection of the above intermediate was carried out in methanol (2 mL) in the presence of 1 mL of concentrated HC1 for 5h. The reaction mixture was evaporated to dryness and the residue was triturated with ether to give a solid. Purification of this material by MPLC on an LH20 column with methanol as the eluent gavē 34 mg of the title compound as a vvhite solid. lH NMR (CD3OD, 400MHz) d 7.35-7.04 (m, 9H), 4.95 (m, 1H), 4.69 (d, 2H), 4.60 (d, 1H), 3.97 (dd, 1H), 3.30-3.10 9m, 3H), 2.82-2.60 9m, 4H), 1.90-1.70 (m, 5H), 1.63 9s, 2H), 1.60 (s,4H), 1.55-1.40 (m, 1H). ΕΧΑΜΡϋΕ B10 icis. dl+d2)
The intermediate prepared from Example B12, Step B (930 mg, mixture of two diastereomers) was dissolved in methanol and hydrogenated over Pd(OH)2 at one atmosphere for 12 hours. The mixture was filtered through Celite and the filtrate concentrated under vacuum to give 700 mg of deprotected product. To the residue (5.5 mg) in 0.5 ml of methylene chloride was added N-BOC-(D)-alanine (4.9 mg), EDC (5.0 mg) and HOBt (3.5 mg). After stirring ovemight, the mixture was poured into water, exacted with methylene chloride and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residure was purified by PLC (hexanes/ethyl acetate=l/l) to give coupling product. A fmal deprotection of the - 154- coupled intermediate was carried out by following the procedure described in Example B19, Step B to give 7.8 mg of desired compound. 1η NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.59 (m, 1 H), 7.39-7.01 (m, 9 H), 5.37 (m, 1/2 H), 5.18 (m, 1/2 H), 4.61 5 (m, 1 H), 4.30 (m, 1/2 H), 4.02-3.61 (m, 3 H), 3.35-2.35 (m, 7 1/2 H), 1.60 (m, 1 H), 1.56 (d, 7 Hz 3/2H), 1.50 (m, 3/2H), 0.95 (m, 3/2 H), 0.88 (m, 3/2 H). FAB-MS: 491.0 (M+l). EXAMPLE B11
To a solution of 0.10g of the compound prepared in Step A 20 of Example B15 in 2mL of chloroform at 0^Cwas added 0.018g of 5-aminomethyltetrazole, 0.027g of HOBT, 0.65mL of triethylamine and 0.048g of EDC and stirred for 10 min. at O^C. lmL of DMF was added to the suspension and stirred ovemight. The reaction mixture was concentrated and the residue was separated by prep TLC (lmm plate) 25 with CHCl3-Me0H-NH40H (90:10:1) as the eluent to give the desired material. FAB MS m/e calcd. for C34H46N8O5 646.36; found 647.2 (m+l).
To a cooled solution of 0.025g of the above product in lmL of ethyl acetate was bubbled in HCl(gas) till it was saturated and allowed 30 to stand at rt for 30 min. The reaction was concentrated to give the title compound. lH NMR (200MHz; CD3OD) indicated a mixture of rotamers; 7.91 (d, J=8 Hz); 7.35-7.06 (m); 5.14 (bs); 4.65-4.48 (m); 3.92 (bt, J=13); 3.72-3.04 (m); 2.76-2.58 (m); 1.95-1.68 (m); 1.61 (s); 1.28 (s). FAB MS Calc. for C34H46N8O5 : MW=546.31; found m/e = (m+l) 547.1. -155- LV 11525 EXAMPLEB12(cis.dl)
Step A-l:
Jboc
To a solution of 3-ethoxycarbonyl-4-piperidone hydro-chloride (11.4 g, 54.9 mmole) in 82 ml of 1N aqueous sodium hydroxide was added di-t-butyl-dicarbonate (12.2 g, 56.0 mmole) in 82 ml of dioxane at room temperature. After 12 hours, the mixture was diluted with ethyl acetate and washed with 0.5 N hydrochloric acid and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. To the crude residue in 200 ml of methylene chloride there was added diisopropylethylamine (14.3 ml, 82.3 mmole) and triflic anhydride (10.1 ml, 60.4 mmole) at -78°C. After 1/2 hour, the mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was washed with IN hydrochloride, brine and dried over magnesium sulfate. The organic layer was concentrated to give the vinyl triflate (21.0 g, 95%). To a - 156 - solution of the vinyl triflate (4.67 g, 11.6 mmole) in 100 ml of methylene chloride and 100 ml of l-methyl-2-pyrrolidinone was added phenyltrimethyltin (2.1 ml, 11.6 mmole), and palladium acetate (0.13 g, 0.58 mmole) at room temperature. After a couple of hours, the reaction was poured into water and extracted with ether (3X). The organic layers were washed with water (3X), brine and dfied over magnesium sulfate. After concentration and purification (MPLC, hexanes/ethyl acetate=10/l), the desired compound was isolated in 83% yield (3.2 g).
Step A:
Jboc
Prepared from the intermediate obtained from Step A-l (3.2 g, 9.66 mmole) which was dissolved in 100 ml of methanol, hydrogenated over Pt02 at one atmosphere for a couple of hours (very slow reaction) and then a portion of Pd/C was added under hydrogen.
The mixture was stirred for 72 hours and then filtered through Celite.
The filtrate was concentrated under vacuum. The residue was purified by MPLC (hexanes/ethyl acetate=10/l) to give the cis compound (1.9 g). -157- LV 11525
StepB:
To intermediate prepared from Step A (200 mg, 0.6 mmole) there was added 2 ml of TFA. After 10 minūtes, the mixture was concentrated and azeotroped with toluene (3X). The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The organic layer was concentrated. To the residue in 10 ml of methylene chloride there was added N-CBZ-D-tryptophan (223 mg, 0.66 mmole), EDC (138 mg, 0.72 mmole), and HOBt (89 mg, 0.66 mmole). After a couple of hours, the reaction was poured into water and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (hexanes/ethyl acetate=2/l) to give two diastereomers in total 66% yield (the less polar diastereomer dl, 82 mg; and the more polar diastereomer d2, 138 mg).
Step C:
H
N
C02Et cis, d1 - 158 -
The less polar diastereomer from Step B (82 mg) was dissolved in 5 ml of methanol and hydrogenated over Pd/C at one atmosphere for a couple of hours (monitored by TLC). The mixture was filtered through Celite and the filtrate concentrated under vacuum. To the 5 residue in 5 ml of chloroform was adc' i N-CBZ-a-methylalanine (38 mg), EDC (31 mg) and HOBt (21 mg). After 3 hours stirring at room temperature, the mixture was poured into vvater, extracted with methylene chloride, and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by 10 chromatatron (hexanes/ethyl acetate=l/l) to give the desired compound in 69% yield (60 mg).
Step D:
The intermediate obtained from Step C was dissolved in 3 ml of methanol and hydrogenated over Pd(OH)2/C at one atmosphere for an hour (monitored by TLC). The mixture was filtered through Celite and the filtrate concentrated under vacuum. The residue was acidified with HC1 in ether to give a white precipitate (dl, 40 mg). iH NMR (400 MHz, CD3OD mixture of rotamers): 7.64 (d, 8 Hz, 1/2 H), 7.57 (d, 8 Hz, 1/2 H), 7.37-7.01 (m, 9 H), 5.28 (dd, 8,5 Hz, 1/2 H), 5.18 (t, 7 Hz, 1/2 H), 4.76 (m, 1 H), 4.30 (m, 1/2 H), 4.15 (m, 1/2 H), 3.81 (m, 2 1/2 H), 3.35 (m, 1/2 H), 3.16 (m, 2 1/2 H), 3.02 (m, 1 1/2 H), 2.98 (m, 1/2 H), 2.45 (m, 1 H), 2.25 (m, 1/2 H), 1.74 (m, 1/2 H), 1.63 (m, 1/2 H), - 159- - 159- LV 11525 1.57 (s, 3/2H), 1.52 (s, 3/2H), 1.49 (s, 3/2H), 1.34 (s, 3/2H), 0.98 (t, 7 Hz, 3/2 H), 0.90 (t, 7 Hz, 3/2 H). FAB-MS: 505.6 (M+l). EXAMPLE B13 (cis. d2)
Prepared from the intermediate obtained from the more polar diastereomer of Example B12, Step B (93 mg) by the procedure described in Example B12 Steps C and D to give the desired compound (d2, 56 mg). iH NMR (400 MHz, CDC13, mixture of rotamers): 7.57(m, 1 H), 7.35-6.94(m, 9 H), 5.37(t, 7 Hz, 2/3 H), 5.17 (m, 1/3 H), 4.61 (m, 1 H), 4.28 (m, 1/3 H), 4.06 (m, 2/3 H), 3.84-3.53 (m, 2 H), 3.28-2.80 (M, 5 H), 2.53 (Μ, 1 H), 1.61 (S, 2 H), 1.51 (S, 1 H), 1.47 (S, 2 H), 1.29 (S, 1 H), 0.95 (t, 7 Hz, 2 H), 0.80 (t, 7 Hz, 1 H). FAB-MS: 505.7. EXAMPLE B14 (trans. dl+d2)
5 -160 -
Step A:
jBOC
A small piece of sodium was added to 2.5 ml of anhydrous ethanol. When the sodium was dissolved, the intermediate from Example B12, Step A (40 mg) was added to the reaction mixture and placed in an 80°C oil bath for 2 hours. This mixture was poured into 0.1N HC1 and extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by PLC (hexanes/ethyl acetate=5/l) to give the trans isomer (26 mg).
Step B:
Prepared from the intermediate obtained from Step A (24 mg) and Intermediate 1 according to the procedures described in Example B7, Steps B and C to give 5.4 mg of product as the hydrochloride salt. lH NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.63-7.35 (m, 2 H), 7.24-6.75 (m, 8 H), 5.01 (m, 1 H), 4.60 (m, 1 H), 4.08-3.68 (m, 3 1/3 H), 3.39-2.41 (m, 5 2/3 H), 1.78-0.96 (1 1/3 H), 1.62 -161 - LV 11525 (s, 3 H), 1.61 (s, 3 H), 0.86 (m, 3 H), 0.66 (m, 1/3 H), -0.10 (m, 1/3 H). FAB-MS: 505.6 (M+l). EXAMPLE B15
Step A:
Approximately 0.250g of the piperidine intermediate prepared in Step A of Example B44 was reacted with 0.39g of Intermediate 3,0.152g of HOBT, 0.17mL of N-methylmorpholine, and 0.225g of EDC in 15mL of chloroform for 18h. The reaction mixture was washed with 0.50N HC1 (lOmL), saturated aqueous NaHC03 (lOmL), dried over MgSC>4 and concentrated. The crude was purified by flash chromatography with hexane-EtOAc (4:1) as the eluent.
To 0.136g of this material in lOmL a 1:1 mixture of methanol-water was added 25mg of lithium hydroxide and stirred ovemight. The reaction mixture was diluted with lOmL of water and - 162 - washed with water, the aqueous layer was acidified to pH=2 with 0.50 N HC1 and extracted with ether (3X1 OmL). The combined organics were washed with brine, dried over MgSC>4 and concentrated to give the desired material as a white solid. - 162 - 10
15
The title compound was prepared from the compound made in Step A by treating it with a saturated solution of HCl(gas) in ethyl acetate for 30min. at RT. Ether was added and the precipitate was flltered and dried. 20 iH NMR (400 MHz, CD3OD mixture of rotamers): 8.10 (t, 1H), 7.78 (dd, 1H), 7.50-7.00 (m, 8H), 4.90 (m, 1H), 4.55 (d, 1H), 3.94 and 3.90 (2 doublets, 1H), 3.80-3.60 (m, 1H), 3.05 (dt, 1H), 2.70-2.50 (m, 4H), 1.90-1.50 (m, 6H), 1.55 (s, 3H), 1.50 (s, 3H), 1.40 (m, 1H). EXAMPLE B16
30 - 163 - - 163 - LV 11525
Step A:
jBOC
To a solution of the intermediate obtained from Example B12, Step A (89 mg, 0.267 mmole) in 2 ml of THF there was added potassium bis(trimethylsilyl)amide (0.5 M, 800 ml, 0.4 mmole) at -78°C. After 1/2 hour, methyl iodide (22 ml, 0.34 mmole) was added to reaction mixture. This reaction was slowly warmed up to room temperature and stirred for additional 12 hours. The mixture was poured into water and then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by a chromatatron (hexanes/ethyl acetate=l/l) to give the desired compound (91 mg, 98%).
Step B:
Prepared from the intermediate obtained from Step A (91 mg) by the procedure described in Example B12, Steps B, C, and D to give the desired compound. -164- 1η NMR (400 ΜΗζ, CD3OD, mixture of diastereomers and rotamers): 7.58 (m, 1 H), 7.37-7.00 (m, 9 H), 5.40-5.23 (m, 1 H),4.60 (m, 1 H), 4.20-3.73 (m, 3 H), 3.40 (m, 1/2 H), 3.15 (m, 2 H), 2.82 (m, 1 H), 2.61-2.30 (m, 2 1/2 H), 1.72 (m, 1/2 H), 1.63-1.29 (m, 6 H), 1.13-0.84 (m, 6 H). EI-MS: 518.2 (M). EXAMPLE B17(cis. dl+d2)
Step A:
[BOC
To a stirred solution of the intermediate prepared from Example B12, Step A-l (1.0 g, 3.02 mmole) in 4 ml of ethanol there was added 4N sodium hydroxide (4 ml). The reaction was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was diluted with water and acidified with 0.5N hydrochloric acid and then exacted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in methanol and hydrogenated over Pd(OH)2 at one atmosphere for 16 hours. The - 165 - LV 11525 mixture was filtered through Celite and the filtrate concentrated under vacuum. To crude acid in 10 ml of chloroform there was added benzyl alcohol (341 ml), EDC (750 mg) and a catalytic amount of DMAP. After 16 hours, the mixture was diluted with methylene chloride and then washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by MPLC (hexanes/ethyl acetate=5/l) to give the desired compound (459 mg, 38%).
Step B:
lBOC
To intermediate prepared from Step A (459 mg, 1.16 mmole) there was added 2 ml of TFA at room temperature. After 10 minūtes, the reaction mixture was concentrated and azeotroped with toluene (3X). To the residue in 10 ml of chloroform there was added Intermediate 1 (433 mg), EDC (265 mg), HOBt (172 mg), and triethylamine (194 ml). The reaction was stirred at room temperature for 3 hours and poured into water. The mixture was extracted with methylene chloride, and dried over sodium sulfate. Concentration and purification (MPLC , hexanes/ethyl acetate= 1.5/1) gavē the coupling product (574 mg) in 76% yield.
Step C: - 166-
To intermediate (10 mg) obtained from Step B there was added TFA at room temperature. After 10 minūtes, the mixture was concentrated to give the desired compound (3 mg). *H NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.62 (m, 1 H), 7.37-6.81 (m, 14 H), 5.42-5.15 (m 1 H), 4.79 (m, 2 H), 4.65 (m, 1 H), 4.32 (m, 1/2 H), 4.12 (m, 1/2 H), 3.27-2.85 (m, 5 1/2 H), 2.55-2.27 (m, 1 1/2 H), 1.74 (m, 1 H), 1.60-1.29 (m, 6 H). FAB-MS: 567.0 (M+l). EXAMPLE B18 fcis.dl+d2)
- 167- 5 10
Step A:
/‘BOC LV 11525
Prepared from the intennediate obtained from Example B17, Step B (20 mg) by the procedure described in Example B8 to give the desired compound.
Step B:
Prepared from the intennediate obtained from Step A by the procedure described in Example B17, Step C to give the desired 30 compound (10 mg). NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.62 (m, 1 H), 7.37-6.98 (m, 9 H), 5.36-5.21 (m 1 H), 4.69 (m, 1/2 H), 4.58 (m, 1/2 H), 4.27-3.91 (m, 2 H), 3.27-2.75 (m, 5 H), 2.51-2.34 (m, 2 H), 1.72 (m, 1 H), 1.58-1.21 (m, 6 H). FAB-MS: 576.9 (M+l). - 168 - Step A: EXAMPLE B19 fcis. dl+d21
15 20
Prepared from the intermediate obtained from Example B18, 25 Step A (142 mg) in 3 ml of methylene chloride to which there was added 2-(methylthio)ethanol (22 ml), EDC (57 mg) and a catalytic amount of DMAP. After 3 hours, the mixture was diluted with methylene chloride and then washed with water and brine. The organic layer was dried over magnesium sulfate, fīltered and concentrated. The residue was purified 30 by PLC (hexanes/ethyl acetate=l/l) to give the desired product (69 mg, 43%). -169- LV 11525
Step B:
Prepared from the intermediate obtained from Step A (50 mg) in 2 ml of ether into which there was bubbled HC1 gas at 0°C. After 30 seconds, the mixture was concentrated to give the white solid (41 mg). iH NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.61(m, 1 H), 7.37-6.97 (m, 9 H), 5.38-5.18 (m 1 H), 4.83-4.54 (m, 1 H), 4.37-3.77 (m, 3 H), 3.57-2.83 (m, 6 H), 2.55-2.21 (m, 3 H), 2.14-1.84 (m, 3 H), 1.72 (m, 1 H), 1.61-1.29 (m, 6 H). FAB-MS: 551.0 (M+l). EXAMPLE B20 (cis. dl+d2)
Prepared from the intermediate obtained from Example B18, Step A (52 mg) in 3 ml of methylene chloride to which there was added ethylamine hydrochloride (9 mg), EDC (21 mg), triethylamine (15 ml) and a catalytic amount of DMAP. After 3 hours, the mixture was diluted - 170 - with methylene chloride and then washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by PLC (methylene chloride/methanol=20/l) to give the coupling product (25 mg). This intermediate by the procedure described in Example B17, Step C gavē the desired compound (25 mg). iH NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.68-6.93 (m, 10 H), 5.34-5.12 (m 1 H), 4.75-4.30 (m, 2 H), 3.50-2.60 (m, 8 H), 1.72-1.17 (m, 8 H), 0.83-0.68 (m, 3 H). FAB-MS: 504.0 (M+l). EXAMPLE B21 (cis.dl+d21
Step A:
Jboc
,OH
To a solution of the intermediate obtained from Example B12, Step A-l (950 mg, 2.87 mmole) in 10 ml of THF there was added diisobutylaluminum hydride (1.0 N in methylene chloride, 8 ml, 8.0 - 171 - LV 11525 mmole) at -78°C. The mixture was stirred at 0°C for 1 hour and then slowly warmed to room temperature. The mixture was quenched with 1N sodium hydroxide, and extracted with ether (3X). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was 5 purified by MPLC (hexanes/ethyl acetate=2/l) to give 617 mg of reduction product.
StepB: 10 15 !boc
CIS rii
Prepared from the intermediate obtained from Step A (57 mg) by hydrogenation under the conditions described in Example B12, Step A to give the desired compound (13 mg).
Step C:
Prepared from the intermediate obtained from Step B (13 mg) by the procedure described in Example B17, Steps B and C to give the desired compound (12 mg). - 172 - 1η NMR (400 ΜΗζ, CD3OD, mixture of diastereomers and rotamers): 7.74-6.80 (m, 10 H), 5.55 (m 1/2 H), 5.20 (m, 1/2 H), 4.66(m, 1 H), 4.11 (m, 1/2 H), 3.93 (m, 1/2 H), 3.20 (m, 3 H), 3.00-2.82 (m, 2 1/2 H), 2.69-2.45 (m, 2 1/2 H), 2.05-1.84 (m, 1 H), 1.68 (s, 3/2 H), 1.61 (s, 3/2 H), 1.60 (s, 3/2 H), 1.47 (s, 3/2 H), 0.90 (m, 1/2 H), 0.17 (m, 1/2 H). FAB-MS: 463.0 (M+l). EXAMPLE B22 fcis. dl+d2)
Prepared from the intermediate obtained from Example B21, 30 Step A (330 mg, 1.14 mmole) in 10 ml of methylene chloride to which there was added acetic anhydride (130 ml), triethylamine (240 ml), and a catalytic amount of DMAP at 0°C. After 1 hour, water was added to the mixture and it was stirred an additional 1 hour at room temperature. The mixture was extracted with methylene chloride and then washed sequentially with 1N sodium hydroxide and brine. The organic layer was - 173 - LV 11525 dried over magnesium sulfate, filtered and concentrated. The residue was hydrogenated under the conditions described in Example B12, Step A to give the desired compound. 5 Step B:
Prepared from the intermediate obtained from Step A (24 mg) by the procedure described in Example B17, Step B and Example B19, Step B to give the desired compound (23 mg). lH NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.74-6.87 (m, 10 H), 5.55-5.16 (m 1 H), 4.65 (m, 1 H), 3.96 (m, 1 H), 3.81 (m, 1/2 H), 3.20 (m, 3 H), 2.86 (m, 1 H), 2.61 (m, 1 H), 2.46 (m, 1/2 H), 2.27 (m, 1/2 H), 2.13 (m, 1 H), 1.98 (s, 1/2 H), 1.93 (s, 1 H), 1.90 (s, 1 H), 1.85 (s, 1/2 H), 1.73-1.30 (m, 7 1/2 H), 0.85 (m, 1/2 H), 0.12(m, 1/2 H). FAB-MS: 505.3 (M+l). 30 - 174 - Step A: EXAMPLE B23 fcis. d\)
mBOC C02Et o
CIS
To intermediate prepared from Example B12, Step A (87 mg) there was added 1 ml of TFA. After 10 minūtes, the mixture was concentrated and azeotroped with toluene (3X). The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The organic layer was concentrated. To the residue in 3 ml of methylene chloride there was added N-BOC-(2R)-amino-5-phenylpentanoic acid (70 mg), EDC (55 mg), and HOBt (35 mg). After a couple of hours, the reaction was poured into water and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated. - 175 - LV 11525
Step B:
JBOC
To intermediate prepared from Step A there was added 1 ml ofTFA. After 10 minūtes, the mixture was concentrated and azeotroped with toluene (3X). To the residue in 3 ml methylene chloride there was added BOC-a-methylalanine, EDC, HOBt, and triethylamine. After a couple of hours, the reaction was poured into water and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (hexanes/ethyl acetate=2/l) to give two diastereomers in 75% yield (the less polar diastereomer dl, 54 mg; the more polar diastereomer d2, 53 mg).
Step C:
To the less polar diastereomer prepared from Step B (54 mg) was added 1 ml ofTFA. After 10 minūtes, the mixture was concentrated - 176 - and azeotroped with toluene (3X). The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether to which was added HC1 in ether to give a white solid 5 (dl, 40 mg). ĪH NMR (400 MHz, CD3OD mixture of rotamers): 7.23 (m, 10 H), 5.08 (m, 1 H), 4.76 (m, 1 H), 4.21 (m, 1 H), 3.80 (m, 2 1/2 H), 3.47 (m, 1/2 H), 3.26-2.99 (m, 4 H),2.86 (m, 1/2 H), 2.63 (m, 2 H), 2.40 (m, 1/2 H), 1.75 (m, 4 H), 1.63 (s, 2 H), 1.60(s, 2 H), 1.57 (s, 2 H), 0.95 (t, 7 Hz, 2 10 H), 0.87 (t, 7 Hz, 1 H). FAB-MS: 494.1 (M+l). EXAMPLE B24 (cis. d2)
The desired d2 compound (40 mg) was prepared from the more polar diastereomer obtained in Example B23, Step B (53 mg) by the 25 procedure described in Example B23, Step C. lH NMR (400 MHz, CD3OD mixture of rotamers): 7.23 (m, 10 H), 4.91 (m, 1 H), 4.75 (m, 1 H), 4.03 (m, 1 H), 3.81 (m, 2 H), 3.45 (m, 1/2 H), 3.26-2.96 (m, 4 H), 2.71 (m, 2 1/2 H), 2.40 (m, 1 H), 1.90-1.64 (m, 4 H), 1.63 (s, 2 H), 1.61 (s, 3 H), 1.59 (s, 3 H), 0.93 (t, 7 Hz, 3 H). FAB-MS: 494.3 (M+l). 30 - 177 - - 177 - LV 11525 EXAMPLE B25 fcis. dl+d2)
To a stirred solution of the intermediate prepared from Example B12, Step A-l in 4 ml of ethanol there was added 4N sodium hydroxide (4 ml). The reaction was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was diluted with water and acidified with 0.5N hydrochloric acid and then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue (100 mg) in 3 ml of methylene chloride therewas added ethylamine hydrochloride (74 mg), EDC (115 mg), HOBt (49 mg) and triethylamine (83 ml). After a couple of hours, the reaction was poured into water and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (hexanes/ethyl acetate=l/l) to give desired compound (74 mg). 5 - 178 -
Step B:
ļBOC
Prepared from the intermediate obtained from Step A (74 mg) by the procedure described in Example B12, Step A to give desired compound (60 mg).
Step C:
Prepared from the intermediate obtained from Step B (60 mg) by the procedure described in Example B23, Steps A, B, and C to give the desired compound (15 mg). iH NMR (400 MHz, CD3OD mixture of diastereomers and rotamers): 7.27 (m, 10 H), 4.91 (m, 1 H), 4.67 (m, 1 H), 3.96 (m, 1 H), 3.42 (m, 1/2 H), 3.26-2.59 (m, 9 1/2 H),1.90-1.64 (m, 4 H), 1.64-1.57 (m, 6 H), 0.79 (t, 7 Hz, 3/2 H), 0.77 (t, 7 Hz, 3/2 H). FAB-MS: 493.3 (M+l). 30 - 179 - - 179 - LV 11525 INTERMEDIATH 4
To a solution of 0.80g of the compound prepared in Step B of Example B7 in 20mL of ethanol was added 0.080g of 20% pallium hydroxide/C and hydrogenated at atmospheric pressure for 3h. The catalyst was filtered through a pad of celite and the filtrate was concentrated to give the title compound. EXAMPLES B26. B27. B28. B29
The following compounds shown in Table B1 were prepared in two steps from Intermediate 4. The acid intermediate in a methylene chloride solution was coupled with alcohols or amines in the presence of EDC and DMAP at ambient temperature and these intermediates were purified and treated with hydrochloric acid(gas) in ethyl acetate to provide the compounds shown in Table B1. - 180 -TABLEB1
Examp!e No. B26 B27 B28 B29
m/e calc. OCH(CH3)2 0(CH2)3CH3
nhch2ch3 C3iH42N404 C33H44N4O4 C33H4SN504 C3iH4iN503 569 560 573.33 531 m/e found (m+1) 570.2 561.1 574.1 532.3 - 181 - LV 11525 EXAMPLE B30
10
Step A:
20 To a solution of l.lg of the piperidine intermediate prepared in Example B7, Step A in 5mL of ethyl acetate at room temperature was bubbled in HC1 (gas) for 10 seconds and stirred for 30 min. The solvent was removed and the oily residue was basified with aqueous sodium bicarbonate solution and extracted with CH2CI2. The combined organics 25 were washed with brine, dried over K2CO3, filtered, and concentrated to give 0.90g of the amine as a thick oil. To a solution of the above intermediate in 20mL of CH2CI2 was added 0.97g of (2R)-N-t-BOC-5-phenylpentanoic acid, 0.45g of HOBT, and 0.80g of EDC and stirred at RT ovemight. The reaction mixture was poured into saturated aqueous 30 sodium bicarbonate solution and extracted with CH2CI2. The combined organics were washed with 0.50N hydrochloric acid solution, brine, dried over MgSC>4, filtered and concentrated. The residue was purified by flash chromatography with hexane-acetone (5:1) as the eluent to yield about 2.0g of the coupled product. -182 -
The above intermediate was treated with 2mL of trifluoroacetic acid in 20mL of CH2CI2 at room temperature for lh. The volatiles were removed on the rotary evaporater and the residue was basified with aqueous NaHC03 and extracted with CH2CI2. The combined organics were dried over K2CO3, filtered and concentrated. The residue was dissolved in CH2CI2 and coupled with 0.60g of N-t-BOC-a-methylalanine in the presence of 0.40g of HOBT and 0.70g of EDC. The reaction was stirred ovemight and worked up as described above. The residue was purified by flash chromatography using hexane-acetone (5:1) as the eluent to give the title compound as a colorless foam. iH NMR (400 MHz, CDCI3 mixture of rotamers): 7.40-6.85 (m, 14 H), 5.10 (s, 2H), 5.05-4.88 (m, 2H), 4.70-4.60 (m, 1H), 3.93 (d, 1/2H), 3.85 (d, 1/2H), 3.10-2.85 (m, 4H), 2.70-2.50 (m, 5H), 1.85-1.60 (m, 7H), 1.50 (s, 3H), 1.48 and 1.47 (2s, 3H), 1.42 (s, 9H), 1.40-1.20 (m, 1H).
dissolved in lmL of ethyl acetate and lmL of saturated HCl(gas) in ethyl acetate was added and stirred for at room temperatūra for 30min. The reaction mixture was cooled to 0°C and ether was added and the solvents vvere evaporated to leave the derired product as a foam. *H NMR (400 MHz, CD3OD mixture of rotamers): 7.40-7.00 (m, 14H), 5.10 (s, 2H), 4.90 (m, 1H), 4.58 (d, 1H), 3.95 and 3.90 (2 doublets , 1H), 3.20-2.95 (m, 4H), 2.80-2.60 (m, 5H), 1.85-1.60 (m, 9H), 1.62 (s, 3H), 1.60 (s, 1H), 1.40 (m, 1H). - 183- - 183- LV 11525 EXAMPLE B31
To 0.90g of the intermediate prepared in Step A Example B30 in 5mL of methanol was added 0.1 Og of 20% palladium hydroxide and hydrogenated at atmospheric pressure ovemight. The catalyst was filtered off through a pad of celite and washed with methanol. The filtrate was concentrated and the residue was dried under vacuum to provide the acid as a colorless foam that was used without purification.
Step B:
- 184 -
To a solution of 0.30g of the acid intermediate prepared in Step A in lOmL of dry THF was added 0.14mL of triethylamine and 0.07mL of ethylchloroformate and stirred for lh. The reaction was quenched with 2mL of aqueous ammonium hydroxide solution and extracted with CH2CI2. The combined organics were washed with 0.50N hydrochloric acid, dried over MgS04 and concentrated. The residue was purified by flash chromatography with chloroform-methanol (95:5) as the eluent to provide a solid that was deprotected with HC1 in ethyl acetate as described above to give the title compound as a white solid. lH NMR (400 MHz, CD3OD mixture of rotamers): 8.15 (t, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.70 (d, 1H), 4.05 and 3.95 (2 doublets, 1H), 3.30-2.95 (m, 4H), 2.90-2.60 (m, 3H), 2.50 (bs, 2H), 1.90-1.65 (m, 7H), 1.60 (2 singlets, 6H), 1.48 (m, 1H). EXAMPLES 32-35 and 49
The compounds described in Table B2 were prepareu from intermediate synthesized in Step A of Example B31 by taking advantage of chemistry used to prepare the title compound in Example B5. Other amines as depicted below were used in place of ethanolamine and the final deprotection was carried in ethyl acetate and dry hydrochloric acid. Ether was generally used to precipitate the hydrochloride salt. LV 11525
Example No. -185 -TABLF. m
nh2 hci FAB MS m/e calc. 632 B33 B34 B49 N(CH3)2 NHtBu
N S NHCH2CH3 C31H44N4O3 C33H48N403 C33H46N4O3S C31H44N4O3 520 548 578 520 ΕΧΑΜΡΕΕ B35
m/e found (m+1) 521.2 549.2 579.2 521.2
To a solution of 0.50g of the acid intermediate prepared in Step A of Example B31 in 5mL of 1,2-dichloroethane was added 0.16g of carbonyldiimidazole and stirred at 60®C for 30min. The reaction was - 186 - cooled to RT, half cc it was then treated with 0.12g of 2-aminopyrazole and heated at 60°C tor lh, cooled to RT and stirred for 2 days. The reaction mixture was poured into 0.50N aqueous hydrochloric acid and extracted with CH2CI2. The combined organics vvere washed with brine, dried over MgS04, concentrated and the residue was purified by flash chromatography with hexane-acetone (1:1) as the eluent. The purified material was deprotected with the HCl/EtOAc protocol as described above to give the title compound as a white solid. FAB MS m/e cacl. (for C32H42N6O3) 558; found 559.2 (m+1) EXAMPLE B36
The title compound was prepared as described in Example B5 but morpholine was used in place of ethanolamine. iH NMR (400 MHz, CD3OD mixture of rotamers): 7.30-6.95 (m, 9H), 4.95 (m, 1H), 4.68 (d, 1H), 4.00 and 3.°5 (2 doublets, 1H), 3.59 (m, 4H), 3.35 (m, 4H), 3.25-2.90 (m, 4H), 2.80 50 (m, 5H), 1.90-1.65 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H), 1.47 (m, 1H). - 187 - LV 11525 EXAMPLE B37
To a stirred solution of 5.0g of the piperidine intermediate prepared in Example B1 Step B was added 5mL of triethylamine at 0°C and 2.8mL of CBZ-C1. The reaction was allowed to warm up to Rt and stir ovemight. The reaction mixture was poured into aqueous ammonium chloride solution and extracted with CH2CI2. The organic layer was washed with 0.50N HC1 solution, dried over MgSCU and concentrated. This crude residue was dissolved in 25 mL of methanol-water and 3eq. of sodium hydroxide was added and stirred for 2h. The reaction mixture was acidified to pH=2 with 2N HC1 and extracted with EtOAc. The combined organics were washed with brine, dried over Na2S04 and concentrated to give the acid as a foam. -188 -
Step B:
To a solution of 0.225g of the above acid intermediate in lOmL of CH2CI2 was added 0.12g of benzenesulfonamide, 0.093g of DMAP and 0.164g of EDC and stirred ovemight. The reaction mixture was washed vvith 0.50N HC1 (2X10mL), dried over Na2S04 and concentrated. The crude residue was dissolved in lOmL of methanol and 0.1 Og of 10% Pd/C and hydrogenated at 40psi ovemight. The catalyst was filtered off through a pad of celite and the filtrate was concentrated to provide the piperidine that was used without purification.
The piperidine intermediate was now coupled to Intermediate 3 and deprotected with HCl/EtOAC as described above to give the title compound as a white solid. FAB MS m/e cacl. (for C35H44N4O5S) 632; found 633.1 (m+1)
EXAMPLE B3R
-189 - LV 11525 5
Step A:
BOC
This intermediate vvas prepared as described in Step A of Example B37 but di-t-butylcarbonate was used in place of CBZ-C1. 10
Step B:
15
To a stirred solution of 2.90g of the acid prepared in Step A in 30mL of dry THF vvas added 2.5mL of triethylamine and 1.25mL of 20 ethylchloroformate and stirred for 30 min. lOmL of the reaction mixture vvas removed. The remaining mixture vvas quenched vvith 20mL of aqueous ammonium hydroxide solution, stirred for 30 min., and extracted vvith EtOAc. The combined organics were vvashed vvith 0.50N HC1, brine, dried over Na2SC>4, filtered and evaporated to give an oily residue. 25 This material vvas dissolved in 20mL of CH2CI2 and 20mL of pyridine at 0°C and 1.1 mL of POCI3 vvas added and stirred for 30min. The reaction mixture vvas poured into brine and vvashed vvith 0.50N HC1 solution, saturated NaHC03 solution, brine, dried over Na2SC>4 and concentrated. Flash chromatography of the residue vvith hexane-ethyl acetate (5:1) as 30 the eluent gavē the desired product. - 190-
Step C:
To a solution of l.Og of the nitrile intermediate prepared in Step B in 20mL of toluene was added 1.96g of trimethyltin azide and heated at reflux for 18h. The excess azide that precipitated upon cooling to room temperature was filtered off. The filtrate was concentrated and spilt in half. To this half was added lOmL of EtOAc and a trace of methanol and HCl(gas) was bubbled in for 5 minūtes and stirred for lh. Ether was added and concentrated to give a gummy material that was \vashed with ether and dried under vacuum to give a brownish solid. 400MHz NMR (CD3OD) revealed that this was the desired tetrazole intermediate.
To 0.30g of the piperidine hydrochloride synthesized above in lOmL of chloroform was added 0.47g of Intermediate 3,0.16g of HOBT, 0.45mL of N-methylmorpholine, and 0.29g of EDC and stirred ovemight. The reaction mixture was poured into 0.50N HC1 solution and extracted with CHCI3. The combined oraganics were washed with brine, dried over Na2S04, and concentrated to give a gummy residue that was purified by flash chromatography with CHCl3-Me0H-NH40H (85:15:1) as the eluent. This provided 0.15g of the desired product. - 191 - LV 11525
Step D:
10
This material was prepared from the mtermediate prepared in Step C by the EtOAc/HCl protocol described above. iH NMR (400 MHz, CD3OD mixture of rotamers): 8.15 (t, 1H), 7.60-7.05 (m, 9H), 4.90 (m, 1H), 4.60 (d, 1H), 4.05 and 3.95 (2 doublets, 1H), 15 3.30-3.10 (m, 4H), 3.10-2.60 (m, 5H), 1.90-1.65 (m, 9H), 1.60 (s, 6H), 1.50 (m, 1H). EXAMPLE B39
To a solution of 0.030g of the intermediate prepared in Step C of Example B38 in 2mL of dry acetone was added 13mg of powdered potassium carbonate and 0.006mL of methyl iodide and stiiTed at RT 30 ovemight. The reaction mixture was poured into brine and extracted with CHCI3. The combined organics were washed with brine, dried over Na2S04, filtered and evaporated to give the alkylated product that was deprotected by the EtOAc/HCl protocol without further purification.
This gavē 0.006g of the title compound as a mixture of isomers. FAB MS m/e cacl. (for C30H41N7O2) 531; found 532.3 (m+1) - 192- EXAMPLE B40
This intermediate was prepared in an analogous manner to the BOC material prepared in Step B of Example B38.
Step B:
To a stirred solution of l.Og of the nitrile from Step A in lOmL of dry ethanol at 0°C was bubbled in HCl(gas) for lh. The reaction was capped and stored in the freezer ovemight. The excess HCl(gas) was removed by bubbling N2 gas for lh and ether was added to inducē precipitation of the imino-ether intermediate, but only an oily material formed. Hence, the solvents were removed on the rotary - 193 - LV 11525 evaporator and the gummy residue was dissolved in CH2CI2 and evaporated twice. Ether was now added and this provided the imino- ether hydrochloride as a foam.
To 0.20g of the above intermediate in 5mL of 5 dichloroethane was added0.073mL of diisopropylethylamine and 0.030g of formylhydrazine and stirred at room temperature ovemight. The reaction mixture was poured into water and extracted with CH2CI2· The combined organics vvere washed with brine, dried over Na2SC>4 and concentrated. The residue thereby obtained was dissolved in 5mL of 10 xylenes and heated at reflux for several hours. The reaction mixture was cooled to room temperature and the xylenes were evaporated. The residue was hydrogenated for 2h in 2mL of methanol and 40mg of 20% palladium hydroxide catalyst. The piperidine thereby obtained was coupled with Intermediate 3 under the Standard EDC/HOBT conditions 15 descnbed earlier. The crude product was purified by flash chromatography with CH2Cl2-Me0H-NH40H (95:5:1) as the eluent. Removal of the BOC protecting group under the EtOAc/HCl conditions gavē the title compound as a white solid. NMR (400 MHz, CD3OD mixture of rotamers): 9.15 (s, 1H), 8.16 20 (bs, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.60 (bs, 1H), 4.10 and 3.95 (2 doublets, 1H), 3.30-3.00 (m, 4H), 3.00-2.60 (m, 5H), 1.90-1.60 (m, 9H), 1.62 (s, 3H), 1.60 (s, 3H), 1.40 (m, 1H). EXAMPLE B41
-194 -
The title compound was prepared in an analogous manner to Example B40 but N-carbomethoxyhydrazine was used in place of N-formylhydrazine. lH NMR (400 MHz, CD3OD mixture of rotamers): 7.30-7.02 (m, 9H), 5 4.90 (m, 1H), 4.60 (d, 1H), 4.05 and 3.95 (2 doublets, 1H), 3.30-2.95 (m, 5H), 2.80-2.60 (m, 4H), 1.90-1.70 (m, 9H), 1.60 (s, 3H), 1.59 (s, 3H), 1.39 (m, 1H). EXAMPLE B42
Step A: 20
25
To a solution of 3.0g of the acid intermediate prepared in Step A of Example B37 in 50mL of benzene was added 0.70mL of oxalyl chloride and 3 drops of DMF and stirred at RT for 2h. The benzene was evaporated off and the residue was dissolved in acetone at 0°C. A solution of 1.59g of sodium azide in 5mL of water was added at stirred at 0°C for lh. The reaction was diluted with ether and water and the organic layer was separated. The organics were washed with brine, dried over Na2S04 and concentrated to give an oily residue. This material was dissolved in dry toluene and heated at reflux for 4h. The reaction mixture 30 -195 - LV 11525 was concentrated and the isocyanate thereby obtained was storred in the refrigerator.
To 0.40g of the isocyanate in toluene was added 0.80mL of triethylamine and 0.20g of methylamine hydrochloride and stirred for ovemight. The reaction mixture was poured into aqueous NaHC03 solution and extracted with EtOAc. The combined organics were washed with brine, dried over MgSC>4 and concentrated to give the methylurea that was used without purification.
The piperidine intermediate prepared in Step A was hydrogenated with Pd(OH)2 in methanol to remove the CBZ protecting group, coupled with Intermediate 3, purified and deprotected with the EtOAc/HCl protocol as described above to give the title compound. 1h NMR (400 MHz, CD3OD mixture of rotamers): 8.10 (m, 1H), 7.40-7.00 (m, 9H), 4.95 (m, 1H), 4.63 (d, 1H), 4.10 and 4.00 (2 doublets, 1H), 3.40-3.10 (m, 4H), 2.85-2.90 (m, 2H), 2.70 (s, 3H), 2.80-2.60 (m, 3H), 1.90-1.62 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H), 1.40(m, 1H). 30 -196- EXAMPLE B43
The isocyanate intermediate prepared (0.20g) in Step A of Example B42 was refluxed in 5mL of 6N aqueous HC1 ovemight. The reaction mixture was washed with ether and the ether layer was discarded. The aqueous layer was basified to pH=10 with aqueous potassium carbonate solution and extracted with CH2C12· The combined organics were washed with brine, dried over K2CO3 and concentrated. This crude amine was converted to the methanesulfonamide by treating it with methanesulfonyl chloride and triethylamine in dichloromethane. After Standard work-up the CBZ group was removed by hydrogenation and elaborated to the title compound as discussed previously. NMR (400 MHz, CD3OD mixture of rotamers): 7.30-7.00 (m, 9H), 4.85 (m, 1H), 4.55 (d, 1H), 4.00 and 3.90 (2 doublets, 1H), 3.30-3.10 (m, 4H), 2.95-2.83 (m, 2H), 2.80 (2 s, 3H), 2.80-2.60 (m, 3H), 1.90-1.65 (m, 9H), 1.60 (s, 3H), 1.56 (s, 3H), 1.55 (m, 1H). EXAMPLE B44
Step A: LV 11525
-197 -HHCI f γ och3
To a solution of 5.0g of the pyridine aldehyde intermediate prepared in Step A of Example B1 in lOOmL of methanol was added 4.0g of sodium cyanide, 5mL of glacial acetic acid and 20g of manganese dioxide and stirred for 2h. The solids were filtered off through a pad of celite and the filtrate was concentrated. The residue was taken up in lOOmL of saturated sodium bicarbonate solution and extracted with 3X100mL of ethyl acetate. The combined organics were washed with brine, dried over Na2S04 and concentrated to provide the pyridine methyl ester. This material was dissolved in methanol and 5mL of saturated HC1 in ethyl acetate was added and concentrated to give the hydrochloride salt.
To 2g of the above pyridine hydrochloride salt in 15mL of methanol was added 0.225g of platinum oxide and hydrogenated at 50psi on the Parr shaker for 2h. The catalyst was filtered off through a pad of celite and washed with methanol. The filtrate was concentrated to give 2.17 of the piperidine hydrochloride as a foam.
Step B:
The title compound was prepared from the compound made in Step A and Intermediate 3 as described previously. - 198 - 1η NMR (400 ΜΗζ, CD3OD mixture of rotamers): 8.10 (t, 1H), 7.78 (dd, 1H), 7.50-7.00 (m, 8H), 4.90 (m, 1H), 4.55 (d, 1H), 3.94 and 3.90 (2 doublets, 1H), 3.85 (s, 3H), 3.80-3.60 (m, 1H), 3.05 (dt, 1H), 2.70-2.50 (m, 4H), 1.90-1.50 (m, 6H), 1.55 (s, 3H), 1.50 9s, 3H), 1.40 (m, 1H). EXAMPLE B45
15
The title compound was prepared from the ester intermediate prepared in Step A of Example B44 in an analogous manner to thc tetrazole compound prepared in Example B38. iH NMR (400 MHz, CD3OD mixture of rotamers): 7.60-7.45 (m, 2H), 20 7.45-7.38 (m, 2H), 7.30-7.10 (m, 5H), 4.90 (m, 1H), 3.95 and 3.90 (2 doublets, 1H), 3.30-3.00 (m, 2H), 2.80-2.55 (m, 4H), 1.90-1.63 (m, 7H), 1.65-1.50 (4 singlets, 6H), 1.40 (m, 1H). EXAMPLE B46
30 -199 - LV 11525
Step A:
BOC NL
OH 5
This compound was prepared in an analogous manner to the 10 protected piperidine acid compound synthesized in Step A of Example B37.
Step B:
HHCI NL
N-N [Η' II H N-N H 15 20
This inteimediate was prepared from the compound synthesized in Step A by using the carbonyldiimidazole method descibed in Example B35, but amino-tetrazole was used in place of aminopyrazole.
Step C:
-200-
This compound was synthesized from the piperidine intermediate made in Step B and Intermediate 3 by using chemistry presented above. FAB MS m/e cacl. (for C28H36N8O3) 532; found 533.1 (m+1) EXAMPLE B47
CBZ
Step A:
OH
To a solation of 0.30g of the imino-ether intermediate prepared in Step B of Example B40 in lOmL of ethanol was added 0.124g of dihydroxyacetone and heated at 60°C under an ammonia atmosphere in a bomb for 16h. The reaction was cooled to room temperature and the solvent was evaporated. The residue was purified by flash chromatography to give 0.129g of the desired product that was stili contaminated with other impurities. -201 - 5
Step B:
LV 11525 10
The intermediate prepared in Step A was elaborated to the title compound after removal of the CBZ protecting group, coupling with Intermediate 3, purification, and a final deprotection with the EtOAc/HCl protocol described earlier. 15 1h NMR (400 MHz, CD3OD mixture of rotamers): 8.18 (2 triplets, 1H), 7.30 (s, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.56-4.55 (singlet overlapping a doublet, 3H), 4.05-3.95 (2 doublets, 1H), 3.30-2.95 (m, 4H), 2.95-2.60 (m, 5H), 1.90-1.65 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H), 1.45 (m, 1H). EXAMPLE B48
30 -202- Step A:
BOC
To a solution of l.Og of the ester prepared in Step B of Example B1 in 50mL of dry THF at 0°C was added 0.20g of lithium aluminum hydride and stirred at room temperature ovemight. The reaction was quenched at O^C with lOmL of water and lOmL of 30% aqueous sodium hydroxide solution. The precipitate was filtered and washed with EtOAc. The ethyl acetate extracts were washed with brine, dried over Na2S04 and concentrated. The crude alcohol was dissolved in 30mL of CH2CI2 and 1.3mL of triethylamine and 1.4g of di-t-butylcarbonate was added at 0°C and then stirred at RT for 2h. The reaction was poured into saturated NaHCC>3 solution and extracted with CH2CI2. The combined organics were washed with 0.50N HC1, brine, dried over Na2S04 and concentrated. This material was purified by flash chromatography with hexane-acetone (5:1) as the eluent.
The alcohol obtained above was dissolved in lOmL of CH2CI2 at 0°C and 0.45mL of triethylamine and 0.14mL of methanesulfonyl chloride were added and stirred for lh. The reaction was diluted with water and extracted with CH2CI2. The combined organics were washed with 0.50N HC1, brine, dried over Na2S04 and concentrated. The crude mesylate was heated at 60°C with 0.20g of the sodium salt of 1,2,4-triazole in lOmL of dry DMF for 3h. The reaction was cooled to RT and quenched with aqueous ammonium chloride solution. The reaction mixture was extracted with ether (3X15mL). The combined organics were washed with brine, dried over Na2S04, filtered and concentrated. This gavē the triazole product that was used without purifīcation. -203 - 5
Step B:
LV 11525 10 15 20 25
The BOC protecting from the piperidine synthesized in Step A was removed with the TFA procedure as described previously and elaborated to the title compound by coupling with Intermediate 3, purifīcation and a final deprotection with the EtOAc/HCl protocol. FAB MS m/e cacl. (for C31H42N6O2) 530; found 531.4 (m+1) EXAMPLE B50
Prepared as described in Example B40 Step B but Intermediate 1 was used in place of Intermediate 3. iH NMR (400 MHz, CD3OD mixture of rotamers): 8.32 and 8.20 (2 doublets, 1H), 7.65 and 7.58 (2 doublets, 1H), 7.40 and 7.35 (2 doublets, 1H), 7.25-7.00 (m, 6H), 6.50 (d, 1H), 5.30-5.20 (m, 1H), 4.58 and 4.55 (2 doublets, 1H), 4.10 and 3.95 (2 doublets, 1/2H), 3.90 (d, 1/2H), 3.40-3.00 (m, 7H), 2.70-2.45 (m, 3H), 2.80-2.50 (m, 2H), 1.60 (s, 6H), 1.34 (d, 1H), 0.95 (d, 1/2H), 0.70 (dt, 1/2H). 30 -204-
EXAMPLE B50 A
To a solution of 0.330g of the acid intermediate prepared in Step A of Example B15 in 3.3mL of dry THF was added 0.196g of carbonyldiiimidazole and heated to 60^0 for 2h. A small aliquot of the reaction mixture was removed and to the remaining solution was added 0. lOmL of 4-aminobutanol and heated for 2h. The reaction mixture was concentrated, taken up in chloroform, washed twice with water, once with 1M K2HPO4, brine, dried over MgS04, filtered and concentrated to provide a residue that was separated by prep TLC (lmm plate ) with CHCl3-Me0H-NH40H (90:10:1) as the eluent to give the desired intermediate.
To a solution of 0.20g of the above material in 2mL of anisole was added 3-4mL of TFA and allowed to stand at rt for 30 min. The volatiles were removed under reduced pressure and the residue was partitioned between chloroform and 1M K?HP04 and basified to pH>9 with NaOH. The organic phase was separated and the aqueous phase was extracted with chloroform, The combined organics were washed with brine, dried over MgS04, filtered and concentrated to provide a gum that was separated by prep TLC (lmm plate ) with CHCl3-Me0H-NH40H (90:10:1) as the eluent to give the desired product. NMR (200MHz; CDCI3 mixture of rotamers): 8.24 (d, J=8); 7.42-7.07 (m); 6.16 ("dd", J=12,4); 4.97-4.8 (m); 4.69 (bd, J=13); 3.93 ("bt", J-10); 3.75-3.64 (m); 3.54-3.4 (m); 3.35-3.16 (m); 3.07 (quart., J=13); 2.77-2.5 (m); 1.97-1.42 (m); 1.34 (s). .FAB MS Calc. for C31H44N4O4 : MW=536.34; found m/e = (m+1) 537.1. -205- LV 11525 A solution of 0.150g of the above free base was lyophillized from 0.50mL of acetic acid and 0.030mL of conc. HC1 to give title compound.
EXAMPLE B50B
15 Prepared in an analogous manner to the compound prepared in Example B50A but ethanolamine was used in place of 4-aminobutanol. NMR (200MHz; CDC13 mixture of rotamers): 8.22 (d, J=8); 7.45-7.05 (m); 6.58 (dt, J=16, 5); 4.88 (bs); 4.64 (bd, J=12); 3.90 (t, J=ll); 3.79 (bs); 3.65-3.50 (m); 3.25-3.15 (m); 3.05 (quart., J=12); 2.8-2.5 (m); 20 2.32 (vbs); 2.0-1.77 (m); 1.77-1.45 (m); 1.35 (s). FAB MS Calc. for C29H40N4O4 : MW=508.30; found m/e = (m+1) 509.2. A solution of 0.029g of the above free base was lyophillized from 0.50mL of acetic acid and O.OlOmL of conc. HC1 to give title compound. 25
EXAMPLE B50C
30 -206- Step A: oh
To a solution of 0.379g of the free base (prepared by basiflcation to pH>9 with NaOH and extraction with CHCI3) of the intermediate prepared in Step P of Example B44 in 20mL of dry THF was added 5.5mL of 1M solution of lithium aluminum hydride in THF and stirred ovemight. The reaction was quenched with lOmL of 30% aqueous NaOH, the organic phase was decanted, and the paste was extracted with ethyl acetate. The combined organics were dried over MgS04 and concentrated. Purification of the residue by prep TLC (lmm plate) gavē the desired amino alcohol. ^H NMR (200MHz; CDCI3 mixture of rotamers): 7.38-7.13 (m); 4.75 (s); 3.22 (bd, J=12 Hz); 3.1-2.92 (m); 2.81 (td, J=10,4 Hz); 2.13 (bs); 1.85-1.6 (m).
Step B:
N H
Cl
The intermediate prepared in Step A was coupled with (2R)-N-t-BOC-5-phenyl pentanoic acid under the Standard EDC/HOBT protocol as described above and purified by prep TLC (lmm plate).
To a solution of 0.145g of the above coupled product in 2mL of CDCI3 was added 0.50mL of 2-chloroethylisocyanate and was heated - 207 - - 207 - LV 11525 at 600C for 6h and allowed to stand at RT ovemight. Prep TLC of this mixture with hexane-EtOAc (1:1) as the eluent gavē 0.1 lg of the desired carbamate. iH NMR (200MHz; CDC13 mixture of rotamers): 7.45-7.05 (m); 5.50 (bd, J=6); 5.19 (s); 5.14 (bs); 4.86-4.45 (bdd?); 4.11 (bd, J=7); 3.93 (bt, J=12); 3.72-3.42 (bm); 3.2-2.88 (m); 2.8-2.5 (bra); 1.95-1.55 (m); 1.44 (s).
The intermediate prepared in Step B was deprotected with EtOAc/HCl and the hydrochloride salt thereby obtained was coupled ith N-t-BOC-a-methylalanine under Standard EDC/HOBT conditions. This material was purified by prep TLC (lmm plate) with hexane-EtOAc (1:1) as the eluent. lH NMR (200MHz; CDCI3 mixture of rotamers): 7.40-7.04 (m); 5.19 (s); 5.17 (bs); 4.98 (s); 4.92 (bs); 4.72 (bd, J=13); 4.54 (bd, J=13); 4.18-4.04 (m); 3.95 (bt, J=13); 3.68-3.45 (m); 3.2-2.85 (m); 2.78-2.47 (m); 2.0-1.6 (m); 1.6-1.4 (m); 1.44 (s).
Approximately 85 mg (0.13 mmoles) of the above productwas taken up in 1.0 mL of DMSO-d6 to which was added 38 mg (0.37 mmoles) of Li0Ac.2H20, and 30 mg (0.2 moles) of NaI; the solution was heated in an 80° C oil bath over night. The reaction mixture was then taken to a gum under a nitrogen stream. It was then partitioned in a mixture of CHCI3 and water, the organic phase separated, dried with anhydrous MgS04, filtered, and after concentration to a gum under reduced pressure, purified by preparātive tic on one 8"x 8" x 1,000m plate in 1:1 EtOAc: hexane to give 85 mg of the title compound. -208- 1η NMR (200MHz; CDCI3 mixture of rotamers) :7.40-7.04 (m); 5.19 (s); 5.17 (bs); 4.98 (s); 4.92 (bs); 4.72 (bd, J=13); 4.54 (bd, J=13); 4.18-4.04 (m); 3.95 (bt, J=13); 3.68-3.45 (m); 3.2-2.85 (m); 2.78-2.47 (m); 2.0-1.6 (m); 1.6-1.4 (m); 1.44 (s).: 7.4-7.0 (m); 7.88-7.69 (bm); 5.4 (s); 5 5.14 (s); 4.95-4.74 (m); 4.67 (bd, J=12); 4.38 (bd, J=13); 4.15-4.02 (m); 3.93 (bt, J=14); 3.50-3.30 (m); 3.18-2.8 (m); 2.75-2.35 (bm); 2.01 (s); 1.9-1.7 (bm); 1.5-1.3 (m); 1.40 (s).
To 49 mg of the intermediate from Step D in 0.5 mL of 2o methanol was added l-2mL of conc. H2SO4. After standing over night a 1M solution of K2HPO4 was added and the reaction mixture was taken to dryness under a stream of nitrogen and the residue was partitioned between CHCI3 and 1M K2HPO4, adjusted to pH >9 with NaOH. The organic phase was removed and the aqueous phase extracted several more 25 times with CHCI3. The combined organic phases were dried with anhydrous MgS04, filtered, and concentrated under reduced pressure.
The resultant gum was subjected to preparative tic on one 8" x 8" x 1,000m silica gel GF plate using 1:10:90 (conc. NH40H:Me0H:CHCl3); two major bands were observed. Isolation of the faster band afforded the 30 title compound. *H NMR (200MHz; CDCI3 mixture of rotamers): 7.4-7.05 (m); 5.44-5.12 (m); 5.18 (s); 5.12-4.8 (m); 5.05 (s); 4.69 (bd, J=12); 4.52 (bd, J=12); 4.12 (bs); 3.93 (bt, J=12); 3.78-3.63 (m);3.44-3.24 (bm); 3.24-2.83 (m); 2.83-2.5 (m); 2.01-1.6 (m); 1.6-1.35 (m); 1.45 (s). FAB MS Calc. for C35H50N4O7 : MW= 638.37; found m/e = (m+1) 639.3. -209- -209- LV 11525 A solution of 23 mg ( 0.042 mmoles) of the above free base in 0.5 mL of acetic acid in a vial was treated with 0.005 mL (0.06 mmoles) of conc. HC1, shell frozen, and lyophyllized ovemight to give the title compound.
EXAMPLE B51 fcis. dO
Step A:
Cīs '^'-'2ΓΊ 6
To a solution of 4.1g of the intermediate prepared in Example B12 Step A-l in 25 ml of ethanol was added 25 ml of 6 N NaOH and stirred 12 hours. The mixture was diluted with water and extracted with ether. The organic layer was discarded. The aqueous layer was cooled to 0°C and acidified with conc. HC1 and then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated to give 2.57g of the cmde acid. The crude acid (438 mg) was dissolved in methanol and hydrogenated over Pd(OH)2 at one atmosphere for 16 hours. The mixture was filtered though Celite and the filtrate was concentrated under vacuum to give the desired compound (370 mg).
J
7d the intermediate prepared in Step A (100 mg) in chloroform was added morpholine (0.35 ml), EDC (95 mg), and HOBt (49 mg). The reaction was stirred for 12 hours at room temperature and was diluted with methylene chloride and then washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purifled by prep TLC (hexanes/ethyl acetate=l/l) to give the desired product (71 mg).
To the intermediate prepared in Step B (71 mg) in ethyl acetate was bubbled in HCl(g) at 0°C for 15 seconds. The mixture was allowed to stand at room temperature for 30min., concentrated to give a solid (64 mg). To this crade material (32 mg) in 2 ml of chloroform was added Intermediate 1 (43 mg), EDC (29 mg), HOBt (15 mg) and triethylamine (21 mL). The reaction was stirred at room temperature for 3 hours and poured into water and extracted with methylene chloride, dried over sodium sulfate and concentrated. Purification (prep TLC, -211- LV 11525 methylene chloride/methanol=20/l) gavē two diastereomers (dļ, the less polar diastereomer, 14 mg; d2, the more polar diastereomer, 16 mg).
Step D:
The less polar diastereomer (dļ, 14 mg) prepared in Step C was dissolved in ethyl acetate and treated with HCl(g) at 0°C for 15 seconds. After 30 minūtes at room temperature the mixture was concentrated to give the desired product (10 mg). FAB-MS: 546.3 (M+l) EXAMPLE B52 (cis. d2)
The title compound (12 mg) was prepared from the more polar diastereomer (d2, 16 mg) obtained in Example B51, Step C by the procedure described in Example B51, Step D. FAB-MS: 546.3 (M+l) -212-
The compounds 1-7 shown in Table B3 were prepared according to the procedures reported above (using different amines in the coupling step). Details are available in Example B51 Steps B, C and D. TABLE B3 η h \ y nh2 hci NJ <f° ° H OO 1 3J fi . sJ R FAB-MS (M+l) 1 di+d2 thiomoīpholine 562.2 2 dļ+d2 pyrrolidine 530.2 3 di+d2 N-methylpiperazine 559.3 4 di+d2 piperidine 544.3 5 dj+d2 ethanjlamine 520.2 6 dj+d2 dimethylamine 504.3 7 di+d2 glycine ethyl ester 562.3 EXAMPLE B53 fcis. dL)
LV 11525
The intermediate prepared from Example B51, Step B in ethyl acetate was treated vvith HCl(g) at 0°C for 15 seconds and allowed to stand at room temperature for 30 min. The mixture was concentrated to dryness to give the crude material. To this crude material (99 mg) in 3 ml of chloroform was added N-t-BOC-0-benzyl-D-serine (107 mg), EDC (92 mg), HOBt (47 mg) and triethylamine (67 ml) and stirred at room temperature for 3 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate, and concentrated. Purification of the residue by RPLC (chromatatron, methylene chloride/methanol=20/l) gavē the desired product (97 mg).
Step B:
The intermediate prepared from Step B (97 mg) in ethyl acetate was treated with HCl(g) at 0°C for 15 seconds and allowed to stand at room temperaturte for 30 minūtes. The reaction mixture was concentrated to give a residue that was dissolved in 2 ml of chloroform -214- and reacted with N-t-BOC-cc-methylalanine (52 mg) in the presence of EDC (62 mg), HOBt (36 mg) and triethylamine (40 ml). After 64 hours at room temperature the reaction mixture was poured into water and extracted with methylene chloride, The combined extracts were drird over sodium sulfate, filtered and concentrated to give a residue that v: s purified by RPLC (chromatatron, methylene chloride/methanol=20 ) to give tvvo diastereomers (dļ, the less polar diastereomer, 65 mg; d2, the more polar diastereomer, 23 mg).
Step C:
The less polar diastereomer (dj, 65 mg) prepared from Step B in ethyl acetate was treated with HCl(g) at 0°C for 15 seconds. After standing at room temperature for 30 minūtes, the mixture was concentrated to give the desired product (58 mg). FAB-MS: 537.4 (M+l) EXAMPLE B54 fcis. di)
- 215 - LV 11525
The title compound (20 mg) was prepared from the more polar diastereomer (d2,23 mg) obtained in Example B53, Step C by the procedure described in Example B51, Step D. FAB-MS: 537.3 (M+l).
The compounds 1-6 shown in Table B4 vvere prepared as described above (with different amines). The details of the syntheses are available in Example B51, Step B and Example B53, Steps A, B and C. TABLE B4
20 R FAB-MS (M+l) 1 di+d2 thiomoīpholine 553.3 2 dj+d2 pyrrolidine 521.3 3 dl N-methy lpiperazine 550.4 4 d2 N-methylpiperazine 550.4 25 5 di+d2 piperidine 535.4 6 di+d2 dimethylamine 495.2 30 -216- ΕΧ AMPLE Β55 (cis. dļ+cb)
The intermediate prepared from Example B51, Step B in ethyl acetate was treated with HCl(g) at 0°C for 15 seconds. The reaction mixture was allowed to stand at room temperature for 30 minūtes and concentrated to give the crude product. To this material (209 mg) in 10 ml of chloroform was added Intermediate 3 (295 mg), EDC (202 mg), HOBt (105 mg) and triethylamine (147 ml) and stirred at room temperatūra for 16 hours and poured into vvater. The mixture was extracted with methylene chloride and dried over sodium sulfate, concentrated and the residue was purifīed by RPLC (chromatatron, methylene chloride/methanol=20/l) to give the desired product (387 mg). This mixture of diastereomers in ethyl acetate was treated with HCl(g) at 0°C for 15 seconds and allowed to stand at room temperatūra for 30 minūtes. The reaction mixture was concentrated to give the desired product (330 mg). FAB-MS: 535.3
The compounds shovvn in Table B5 were prepared according to established procedūras (with ethanolamine instead of morpholine) as exemplified in Example B51, Step B and Example B53, Steps A, B and C using Intermediate 3. -217- LV 11525 5 10 1 di 2 d2 TABLE B5
ethanolamine 509.2 EXAMPLE B56 (cis. dj+d?')
To the intermediate prepared in Example B51, Step A (1.15 g) in benzene (80 ml) was added oxalyl chloride (365 ml) and DMF (2 drops) at 0°C and stirred at 0°C for 10 minūtes and room temperature for 2 hours and concentrated to give the acyl chloride. To a solution of acyl -218- chloride at 0°C in acetone (10 ml) was added sodium azide (741 mg) in water (3 ml) and stirred at room temperature for 45 minūtes. The mixture was extracted with ether, vvashed with water, brine, dried over MgS04, filtered and evaporated to give the acyl azide which was dissolved in toluene (35 ml) and was refluxed 12 hours to give the isocyanate (1.02 g).
Step B:
H HCI I
A solution of the intermediate prepared in Step A (55 mg) and 2-(methylthio)ethylamine (147 mg) in toluene (5 ml) was refluxed for one hour. The reaction was quenched with IN HCI and extracted with ether and then dried over sodium sulfate. Concentration and purification (chromatatron, methylene chloride/methanol=20/l) gavē the desired urea. Deprotection of the BOC protecting group under conditions described above gavē the desired product (40 mg).
To the intermediate prepared in Step B (20 mg) in 2 ml of chloroform was added Intermediate 1 (28 mg), EDC (19 mg), HOBt (10 mg) and triethylamine (14 ml). The reaction was stirred at room - 219 - LV 11525 temperature for 16 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Concentration and purification (chromatatron, methylene chloride/methanol=20/l) gavē desired product The mixture was treated with HC1 in EtOAc to give the final product (6 mg). FAB-MS: 565.3 (M+l)
The compounds shown in Table B6 were prepared according to established procedures (with different amines or alcohol). 10 15 20 TABLE B6
25 R FAB-MS (M+l) 1 dl+d2 ethanol 520.3 2 dl+d2 morpholine 561.4 3 dl+d2 ethanolamine 535.3 4 dl+d2 ethylamine 519.2 EXAMPLE B57 fcis. dl+d2^
-220-
To a solution of the intermediate prepared from Example B56, Step B (20 mg) in 1 ml of chloroform was added Intermediate 3 (28 mg), EDC (19 mg), HOBt (10 mg) and triethylamine (14 ml). The reaction was stirred at room temperature for 16 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Concentration and purification (chromatatron, methylene chloride/methanol=20/l) gavē the desired product Deprotection of this diastereomeric mixture with HCl/EtOAc gavē the final product (8 mg). FAB-MS: 554.4 (M+l)
The compounds shown in Table B7 were prepared according the above-described procedures (with ethanol and different amines). TABLE B7
R FAB-MS (M+l) 1 dl+d2 ethanol 509.3 2 dl+d2 morpholine 550.4 3 dl+d2 ethanolamine 524.3 4 dl+d2 thiomoīpholine 566.2 -221 - LV 11525 EXAMPLE B58 (trans, dl+d2)
To a solution of the intermediate prepared from Example B14, Step A (2.52 g) in ethanol was added 6N NaOH. The mixture was 20 refluxed for 3 hours and then concentrated. The residue was diluted with water and acidified with 0.5 N hydrochloric acid and extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated to give the desired product (2.12 g). 25 Step B: BOC i
To a solution of the intermediate prepared from Step A (15 mg) in 1 ml of chloroform was added 4-amino-l-butanol (9 ml), EDC (19 mg), and HOBt (7.5 mg). The reaction was stirred at room temperature -222- for 2 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Concentration and purifīcation (chromatatron, methylene chloride/methanol=20/l) gavē the desired product.
10 15 20
The intermediate prepared from Step B was deprotected with the HCl/EtOAc protocol. To this crude material in 1 ml of chloroform was added Intennediate 1 (18 mg), EDC (19 mg), HOBt (7.5 mg) and triethylamine (20 ml). The reaction was stirred at room temperature for 4 hours and poured into water. The mixture was extracted with methvlene chloride and dried over sodium sulfate. Concentration and purifīcation (PLC, methylene chloride/methanol=10/l) gavē the desired product (20 mg, unseparable diastereomer mixture) that was treated with HC1 (gas) in EtOAc to give the desired product (18 mg). 25 1h NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers): 7.73 (d, 8 Hz, 1/2 H), 7.65 (d,8 Hz, 1/2 H), 7.54-6.98 (m, 7 1/2 H), 6.87 (t, 7 Hz, 1 1/2 Hz), 5.25 (m, 1 H), 4.53 (m, 1 H), 3.89 (m, 1 H), 3.39-2.47 (m, 10 H), 1.71-0.93 (m, 5 H), 1.61 (s, 3/2H), 1.60 (s, 3 H), 1.58 (s, 3/2 H), 0.41 (m, 1/2 H), 0.11 (m, 1/2 H). FAB-MS: 548.2 (M+l).
The compounds shown in Table B8 were prepared according to the above procedures (with different amines). 30 LV 11525 -223-TABLE B8
R FAB-MS (M+l) 1 dl+d2 ethylamine 504.3 2 dl+d2 morpholine 546.3 3 dl+d2. ethanolamine 520.2 4 dl H2N^f N — H 556.1 5 d2 556.1 H2N"'~Xf ^
N—J H EXAMPLE B59 itrans. d2)
trans, d2 30 -224-
Step A:
BOC
I
.NL ( 1 ?H3 y^8'0 * v"CH3 trans ^h3
To a solution of the intermediate prepared from Example B58, Step A (915 mg) in chloroform was added (IR, 2R)-N-methyl pseudoephedrine (590 ml), EDC (1.14 g), and a catalytic amount of DMAP. The reaction was stirred at room temperature for 12 hours and poured into water. The mixture vvas extracted with methylene chloride and dried oyer sodium sulfate. Concentration and purification (MPLC, hexanes/ethyl acetate=3/l) gavē two diastereomers (dl, the less polar diastereomer, 316 mg; d2, the more polar diastereomer, 138 mg).
Step B:
BOC
A solution of the more polar intermediate prepared in Step A (138 mg) in methanol was hydrogenated with Pd(OH)2/C at one atmosphere for a couple of hours. The mixture was filtered through Celite and the fīltrate was concentrated. The residue was redissolved in ether and washed with IN hydrochloric acid. The aqueous layer was discarded. The organic layer was dried over sodium sulfate, filtrated and concentrated to give the desired product (84 mg). -225- LV 11525
Step C:
BOC
To the intermediate prepared from Step B (16 mg) in 10 chloroform was added glycine ethyl ester hydrochloride salt (21 mg), EDC (19 mg), HOBt (13 mg) and triethylamine (35 ml). After 3 hours at room temperature the mixture was diluted with methylene chloride and then washed with water and brine. The organic layer was dried over sodium sulfate, fīltered and concentrated. The residue was purifīed by 15 prep TLC (hexanes/ethyl acetate=l/l) to give the desired product (16 mg).
Step D:
The intermediate prepared in Step C (8 mg) was treated with HCl(gas) in EtOAc to give a crude hydrochloride. To this cmde material in 1 ml of chloroform was added intermediate 1 (8 mg), EDC (8 mg), HOBt (5 mg) and triethylamine (8 ml). The reaction was stirred at room temperature for 12 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Concentration and purification (PLC, hexanes/ethyl acetate=l/2) gavē the -226- desired product which was deblocked with the HCl/EtOAc protocol to give the desired product (11 mg). iH NMR (400 MHz, CD3OD, :~.iixture of rotamers): 7.73 (d, 8 Hz, 1/2 H), 7.54 (d, 8 Hz, 1/2 H), 7.38-6.99 (m, 8 H), 6.84 (d, 7 Hz, 1 H), 5.28- 5 5.05 (m, 2 H), 4.80-4.52 (m, 1 H), 4.09 (m, 3 H), 3.59 (m, 1 1/2 H), 3.34 (m, 1 1/2 H), 3.24 (m, 1 H), 2.98 (m, 1 H), 2.70-2.48 (m, 2 1/2 H), 1.70- 1.55 (m, 1 1/2 H), 1.61 (s, 3 H), 1.60 (s, 3 H), 1.22 (t, 7 Hz, 3 H), 1.00 (m, 1/2 H), 0.57 (m, 1/2 H). FAB-MS: 562.3 (M+l) 10
The compounds shovvn in Table B9 were prepared according to the above procedure shown in Example B59. ^BLE B9
15 20 FAB-MS (M+l) 576.3 562.3
R 25 1 d2 2 d2 β-alanine ethyl ester L-alanine methyl ester 30 -227- -227- LV 11525 EXAMPLE B60 Ttrans. d2)
The intermediate prepared in Example B59, Step C (8 mg) in ethyl acetate was treated with HCl(g) at 0°C for 15 seconds and maintained at room temperature for 30 minūtes, concentrated to dryness to give the crude material. To this crude material in 1 ml of chloroform was added intermediate 3 (8 mg), EDC (8 mg), HOBt (5 mg) and triethylamine (8 ml). The reaction was stirred at room temperature for 12 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Concentration and purification (PLC, hexanes/ethyl acetate=l/2) gavē the desired product which was treated with HCl(gas) in EtOAc to provide the title compound (11 mg). FAB-MS: 551.4 (M+l)
The compounds shown in Table B10 were prepared according to the above procedure (coupled with different amino acids). TABLE B10
trans, d2 -228- R FAB-MS (M+l) 1 d2 β-alanine ethyl ester 565.4 2 d2 L-alanine methyl ester 551.4 EXAMPLE B61 (trans. dl-Ki2)
BOC i
Step A:
To a solution of the intermediate prepared in Example B12, Step A (200 mg) in methanol was added a catalytic amount of sodium methoxide in methanol and refluxed for a couple of hours. The mixture was poured into 0.1 N hydrochloric acid and extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated to give the desired product (190 mg). LV 11525
To a solution of the intermediate from Step A (120 mg) in 2 ml of toluene was added diisobutylaluminum hydride (1N in hexanes, 0.49 ml) at -78°C. After the reaction vvas stirred at -78°C for 1 hour it was quenched with methanol and then poured into 0.5 N hydrochloric acid solution. The mixture vvas extracted with ether. The organic layer vvas dried over sodium sulfate, filtered and concentrated. The residue vvas purifīed by PLC (hexanes/ethyl acetate=3/l) to give the desired product (60 mg).
BOC I
Step C:
To a solution of triethyl phosphonoacetate in THF (5 ml) vvas added potassium bis(trimethylsilyl)amide (0.5 N in toluene, 1.45 ml) at 0°C. After 1 hour at room temperature the intermediate from Step B (42 mg) in THF (1 ml) vvas added to the phosphorane solution and refluxed for an hour. This mixture vvas concentrated and the residue vvas purifīed by PLC (hexanes/ethyl acetate=4/l) to give the desired product (50 mg). -230-
Step D:
To the intermediate prepared in Step C (50 mg) was added 0.5 ml ofTFA at room temperature. After 10 minūtes, the mixture was concentrated and azeotroped with toluene (3X). To a solution of the residue in 1 ml of chloroform was added Intermediate 1 (62 mg), EDC (53 mg), HOBt(23 mg) and triethylamine (58 ml). The mixture was stirred at room temperature for 3 hours and poured into water. The mixture was extracted with methylene chloride, and dried over sodium sulfate. Purification (PLC, hexanes/ethyl acetate=l/l) of the residue gavē the coupled product (65 mg).
A solution of the intermediate prepared from Step D (50 mg) in methanol was hydrogenated with Pd(OH)2/C at one atmosphere for a couple of hours. The mixture was filtered through Celite and the filtrate -231 - -231 - LV 11525 was concentrated. The residue was treated with HCl(gas) in EtOAc to give the desired product (36 mg). FAB-MS: 533.3 (M+l) EXAMPLE B62 iris, dll
Step A: C02Et
Ethyl chloroformate (12.9 ml) was added to a stirred suspension of cuprous chloride (1.35 g) in THF (200 ml). At 0°C, a solution of ethyl nicotinate was added slowly followed by the addition of Grignard reaģent (prepared from 2-bromobenzaldehyde (25 g), 1,3-propandiol (20 ml), and magnesium (4.9 g) by the procedure described in J. Org. Chem.. 51,3490 (1986)). The reaction was stirred for an hour and poured into a saturated ammonium chloride/ammonia solution (1/1) and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and brine and dried over sodium sulfate. Evaporation of the solvent gavē the desired product. Crystallization of this material from ethyl acetate gavē 25g of the desired material. -232-
Step B:
H I
Et02C
The intermediate prepared in Step A (25 g) was dissolved in hot ethyl acetate (500 ml) and then cooled down to room temperature. This organic solution was hydrogenated with Pt02 at one atmosphere for a couple of hours (monitored by TLC). The mixture was filtered through Celite and the filtrate concentrated under vacuum. The residue was dissolved in hot ethanol (150 ml) was treated with 6N NaOH (75 ml) at reflux for 10 minūtes. The mixture was concentrated under vacuum and to the residue vvas added water and stirred at room temperature for 10 minūtes. The pale white solid was collected by filtration. The filtrate was extracted with methylene chloride and washed with brine and dried over sodium sulfate. The solvent was concentrated and combined with pale white solid to give 13.6 g of desired product.
Step C: CBZ i
Et02C
To a solution of the inten ediate prepared in Step B (10.1 g) in THF (300 ml) at 0°C was added a catalytic amount of indicator (bromocresol green) and NaCNBH3 (64 mmole). To this reaction mixture was added 1 N hydrochloric acid till a yellow color pērsi sted (pH=4.0). After an hour, the mixture was poured into 1 N NaOH and extracted with chloroform. The organic layer was washed with brine -233 - LV 11525 dried over sodium sulfate and concentrated. The residue was purified by filtration through silica gel with methylene chloride/methanol=10/l to remove very polar material. The material obtained after concentration of the filtrate was dissolved in chloroform and to this mixture was added triethylamine (6 ml) and CBZ-C1 (4.6 ml) at 0°C. After stirring for 15 minūtes, the reaction was poured into water and extracted with methylene chloride. The organic layer was washed with brine, dried over sodium sulfate. Concentration and purification (MPLC, hexanes/ethyl acetate=5/l) gavē the desired product (6.4 g).
Step D:
CBZ
To a solution of the intermediate prepared from Step C (2.17 g) in methanol (30 ml) vvas added 1 N hydrochloric acid (5 ml) and stirred for an hour. The mixture was poured into IN NaOH solution and extracted with ether. The organic layer vvas vvashed with brine and dried over magnesium sulfate. Purification of the residue (chromatatron, hexanes/ethyl acetate=5/l) gavē the desired product (1.56 g).
Step E:
CBZ Et02C
<*s.C02Et
To a solution of triethyl phosphonoacetate in THF (25 ml) vvas added potassium bis(trimethylsilyl)amide (0.5 N in toluene, 4.56 ml) -234- at 0°C. After stirring an hour at room temperature the intermediate from Step D (860 mg) in THF (10 ml) was added to the phosphorane solution at room temperature. The mixture was stirred at room temperature for an hour and then quenched with 1 N hydrochloric acid. This mixture was extracted with ether, washed with brine, and dried over magnesium sulfate. Purification of the residue (chromatatron, hexanes/ethyl acetate=5/l) gavē the desired product (873 mg).
The intermediate prepared in Step E (870 mg) was dissolvt in methanol and hydrogenated with Pd(OH)2/C at one atmosphere for one and one-half hours, The mixture was filtered through Celi te and the filtrate was concentrated under vacuum. To the residue in chloroform was added intermediate 3 (749 mg), EDC (714 mg) and HOBt (276 mg) and stirred for 2h. The mixture was concentrated and purified (chromatatron, hexanes/ethyl acetate=2/l) to give two diastereomers (545 mg, the less polar diastereomer, dl; 500 mg the more polar diastereomer, d2). - 235 - LV 11525
10
To a solution of the less polar diastereomer prepared in Step F (200 mg) in ethyl acetate was bubbled in HCl(g) at 0°C for 15 seconds. After standing for 30 minūtes at room temperature the mixture was concentrated and purified (LH-20, 100% methanol) to give the cis, dl 15 product as a vvhite solid (100 mg). lH NMR (400 MHz, CD3OD, mixture rotamers): 7.28-7.06 (m, 9 H), 5.09 (m, 1/2 H), 4.85-4.55 (m, 1 1/2 H), 4.17 (m, 1 H), 4.10 (q, 7 Hz, 2 H), 3.77 (m, 2 H), 3.46 (m, 1 1/2 H), 3.25 (m, 1/2 H), 3.15-2.39 (m, 9H), 1.89-1.60 (m, 5 H), 1.65 (s, 2 H), 1.62 (s, 2 H), 1.57 (s, 2 H), 1.21 (t, 7 20 Hz, 3 H), 0.91 (t, 7 Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H). FAB-MS: 594.3 (M+l) EXAMPLE B63 (cis. d2)
-236-
The desired cis, d2 product (3.3 mg) was obtained from the more polar diastereomer obtained in Example B62, Step F by the procedure described in Example B62, Step G. iH NMR (400 MHz, CD3OD, mixture rotamers): 7.90-7.03 (m, 9 H), 4.92-4.61 (m, 2 H), 4.10 (q, 7 Hz, 2 H), 4.07 (m, 1 H), 3.79 (m, 2 H), 3.45 (m, 1 1/2 H), 3.25 (m, 1/2 H), 3.07-2.38 (m, 9H), 1.94-1.69 (m, 4 H), 1.63 (s, 3/2 H), 1.61 (s, 3/2 H), 1.60 (s, 3/2 H), 1.59 (s, 3/2 H), 1.20 (t, 7 Hz, 3 H), 0.91 (t, 7 Hz, 3 H). FAB-MS: 594.3 (M+l).
Step A: EXAMPLE B64 (cis. dl)
To the less polar diastereomer prepared in Example B62, Step F (30 mg) in ethanol (1 ml) was added 6 N NaOH (30 ml) at room temperature. After stirring for an hour the mixture was concentrated. To the residue was added 1 N hydrochloric acid and extracted with ethyl -237- LV 11525 acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the desired product (20 mg).
15 To a solution of the intermediate prepared in Step A (6 mg) in 0.5 ml of chloroform was added ethanolamine (0.8 ml), EDC (3.5 mg), and HOBt (1.8 mg). The reaction vvas stirred at room temperature for a couple of hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Concentration and 2o purification (PLC, methylene chloride/methanol=20/l) provided the coupled product. This material was deprotected with HC1 in EtOAc to give the desired cis, dl product (1.6 mg). iH NMR (400 MHz, CD3OD, mixture rotamers): 7.28-7.07 (m, 9 H), 5.09 (m, 1/2 H), 4.85-4.62 (m, 1 1/2 H), 4.19 (m, 1 H), 3.75 (m, 2 H), 25 3.55 (t, 6 Hz, 2 H), 3.45 (m, 1 H), 3.34-2.84 (m, 6 1/2 H), 2.73-2.45 (m, 5 1/2 H), 1.85-1.57 (m, 5 H), 1.65 (s, 3/2 H), 1.62 (s, 3/2 H), 1.57 (s, 3/2 H), 1.56 (s, 3/2 H), 0.92 (t, 7 Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H). FAB-MS: 609.2 (M+l) 30 -238- -238- EXAMPLE Β65 (cis. dl)
10
To a solution of the intermediate prepared in Example B64 Step A (6 mg) in 0.5 ml of chloroform was added ethylamine hydrochloride salt (1 mg), EDC (3.5 mg), triethylamine (4 ml) and HOBt (1.8 mg). The reaction was stirred at room temperature for a couple of 15 hours and poured imo water, and extracted with methylene chloride and dried over sodium sulfate. Purification of the residue (PLC, methylene chloride/methanol=20/l) gavē the coupled product. This material was treated with HC1 in EtOAc to yield the desired cis, dl product (1.5 mg). lH NMR (400 MHz, CD3OD, mixture rotamers): 7.28-7.07 (m, 9 H), 20 5.09 (m, 1/2 H), 4.83-4.62 (m, 1 1/2 H), 4.17 (m, 1 H), 3.75 (m. 2 H), 3.50 (m, 1 1/2 H), 3.25-2.84 (m, 6 1/2 H), 2.72-2.39 (m, 5 H), 1.89-1.58 (m, 5 H), 1.65 (s, 3/2 H), 1.61 (s, 3/2 H), 1.57 (s, 3/2 H), 1.56 (s, 3/2 H), 1.06 (t, 7 Hz, 3 H), 0.91 (t, 7 Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H). FAB-MS: 593.3 (M+l) 25 EXAMPLEB66 (cis. dn
30 -239- LV 11525
To a solution of the intermediate prepared from Example B64, Step A (8 mg) in methylene chloride (1 ml) was added ethyl chloroformate (2.3 ml) and triethylamine (5 ml) at 0°C. The reaction mixture was stirred at 0°C for 10 minūtes and room temperature for an hour. The mixture was poured into saturated sodium bicarbonate and extracted with methylene chloride. The organic layer was washed with brine and dried over sodium sulfate, and concentrated. To the residue in acetone (0.5 ml) was added sodium azide (2.3 mg) in vvater (0.2 ml) at 0°C. After stirring at room temperature for an hour the mixture was extracted with ether, washed with water and brine, and dried over MgSC>4. Filtration and evaporation gavē acyl azide which was dissolved in toluene (1 ml) and refluxed for 3 hours to give the isocyanate. The toluene solution was cooled down to room temperature and methylamine (40% in water, 9 ml) was added. After stirring for 12 hours in room temperature, the reaction was quenched with 1 N HC1 and extracted with methylene chloride and then dried over sodium sulfate and concentrated. Purification of the residue (PLC, methylene chloride/methanol=20/l) gavē desired urea which was deprotected with HC1 in EtOAc to yield the desired product (3.5 mg). FAB-MS: 594.3 (M+l). EXAMPLE B67 fcis. dl+d2)
The intermediate prepared in Example B62, Step E (17 mg) was dissolved in methanol and hydrogenated with Pd(OH)2/C at one atmosphere for one and half hours. The mixture was Filtered through Celite and the filtrate was concentrated under vacuum to give the free -240- amine (11 mg). To this free amine (5.5 mg) in chloroform was added Intermediate 1 (7 mg), EDC (6 mg) and HOBt (4 mg). After 12 hours, the mixture was concentrated and purified (chromatatron, hexanes/ethyl acetate=2/l) to give an inseparable mixture of diastereomers. This diastereomeric mixture in ethyl acetate was treated with HCl(g) at 0°C for 15 seconds. After standing for 30 minūtes at room temperature, the mixture was concentrated to give a white solid (8 mg). FAB-MS: 605.3 (M+l) EXAMPLE B68 fcis. dl)
To a solution of diethyl cyanomethyl phosphonate in THF (25 ml) was added potassium bis(trimethylsilyl)amide (0.5 N in toluene, 3.44 ml) at 0°C. After stirring an hour at room temperature the intermediate from Example B62, Step D (650 mg) in THF (10 ml) was added to the phosphorane solution at room temperature. The mixture was stirred at room temperature for an hour and then quenched with 1 N hydrochloric acid. This mixture was extracted with ether and washed with brine, and dried over magnesium sulfate and concentrated. -241 - -241 - LV 11525
Purification (chromatatron, hexanes/ethyl acetate=5/l) gavē the α,β-unsaturated nitrile (trans, 466 mg; cis, 124 mg).
The intermediate prepared in Step A (590 mg) was dissolved in methanol and hydrogenated with Pd(OH)2/C at one atmosphere for one and half hours. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. To the residue in chloroform was added intermediate 3 (560 mg), EDC (560 mg) and HOBt (208 mg). After a couple of hours, the mixture was concentrated and purified (chromatatron, hexanes/ethyl acetate=l/l) to give two diastereomers (220 mg, the less polar diastereomer, dl; 260 mg the more polar diastereomer, d2).
Step C:
To the less polar diastereomer prepared in Step B (220 mg) in toluene (5 ml) was added trimethyltin azide (206 mg) and refluxed for -242- 6 1/2 hours. The solvent was removed under vacuum. The residue was redissolved in methylene chloride/methanol/acetic acid=20/l/0.1 (20 ml) and allowed to stand at room temperature for 12 hours and the solvent was removed under vacuum. The residue was purified by PLC (methylene chloride/methanol/acetic acid=20/l/0.1) to give the desired product (120 mg).
The intermediate in Step C (120 mg) was treated with HC1 in EtOAc to give the desired cis, dl product as a white solid (98 mg). iH NMR (400 MHz, CD3OD, mixture of rotamers): 7.28-7.08 (m, 9 H) 5.08 (m, 1/2 H), 4.84-4.53 (m, 1 1/2 H), 4.18 (m, 1 H), 3.78 (m, 3 H), 3.27-3.03 (m, 6 H), 2.85-2.30 (m, 4 H), 1.90-1.38 (m, 5 H), 1.65 (s, 3/2 H), 1.61 (s, 3/2 H), 1.57 (s, 3/2 H), 1.56 (s, 3/2 H), 0.90 (t, 7 Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H). FAB-MS: 590.2 (M+l). -243- LV 11525 EXAMPLE B69 (cis. d2)
The desired product (2 mg) was prepared from the more polar diastereomer (6.8 mg) obtained in Example B68, Step B by the procedure described in Example B68, Step C and D. FAB-MS: 590.4 (M+l).
Step A: EXAMPLE B70 fcis. ā\)
-244-
The intermediate prepared in Example B68, Step A (782 mg) was dissolved in methanol and hydrogenated with Pd(OH)2/C at one atmosphere for one and one-half hours. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. To the residue in chloroform was added Boc-D-Tryptophan (468 mg), EDC (534 mg) and HOBt (207 mg). After a couple of hours, the mixture was concentrated and purified (MPLC, hexanes/ethyl acetate=l/l) to give two diastereomers (316 mg, the less polar diastereomer, dl; 300 mg the more polar diastereomer, d2).
Step B:
The less polar diastereomer from Step A (316 mg) in ethvl acetate was treated with HCl(g) at 0°C for 15 seconds. After standing 30 minūtes at room temperature, the mixture was concentrated to dried to give crude material. To the residue in 5 ml of chloroform was added N-Boc-a-methylalanine (158 mg), EDC (149 mg), triethylamine (217 ml) and HOBt (77 mg) and stirred for 12 hours at room temperature. The mixture was poured into water and extracted with methylene chloride and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatatron (hexanes/ethyl acetate=l/2) to give the desired compound (287 mg). -245 - LV 11525
Step C:
The desired cis, dl product (135 mg) was prepared from above intermediate (287 mg) prepared in Example B70, Step B by the procedure described in Example B68, Steps C and D. lH NMR (400 MHz, CD3OD, mixture rotamers): 8.09 (d, 8 Hz, 1/2 H), 15 7.80 (d, 8 Hz, 1/2 H), 7.64 (d, 8 Hz, 1/2 H), 7.57 (d, 8 Hz, 1/2 H), 7.35 (d, 7 Hz, 1 H), 7.22-7.00 (m, 7 H), 5.31-5.20 (m, 1 H), 4.71 (d, 12 Hz, 1/2 H), 4.41 (d, 12 Hz, 1/2 H), 4.15 (m, 1/2 H), 3.92-3.67 (m, 2 1/2 H), 3.43-3.03 (m, 8 1/2 H), 2.80 (m, 1 H), 2.52-2.25 (m, 1 1/2 H), 1.59 (s, 3/2 H), 1.54 (s, 3/2 H), 1.50 (s, 3/2 H), 1.35 (3/2 H), 1.43 (m, 1 H), 0.93 (t, 7 Hz, 20 3/2 H), 0.84 (t, 7 Hz, 3/2 H). FAB-MS: 601.1 (M+l). EXAMPLE B71 fcis. d2)
The title product (125 mg) was prepared from the more polar diastereomer (300 mg) prepared in Example B70, Step A by the -246- procedure described in Example B70, Step B and Example B68, Steps C and D. 1η NMR (400 MHz, CD3OD, mixture rotamers): 8.24 (d, 8 Hz, 1/2 H), 8.09 (d, 8 Hz, 1/2 H), 7.59 (d, 8 Hz, 1/2 H), 7.54 (d, 8 Hz, 1/2 H), 7.34-5 6.92 (m, 8 H), 5.40 (m, 1/2 H), 5.15 (m, 1/2 H), 4.64 (d, 13 Hz, 1/2 H), 4.55 (d, 13 Hz, 1/2 H), 4.22 (m, 1/2 H). 4.09 (m, 1/2 H), 3.81-3.58 (m, 2 1/2 H), 3.40-2.84 (m, 9 1/2 H), 2.71-2., 2 (m, 1 1/2 H), 1.63 (s, 3/2 H), 1.52 (s, 3/2 H), 1.48 (s, 3/2 H), 1.29 (3/2 H), 1.53 (m, 1/2 H), 1.32 (m, 1/2 H), 0.90 (t, 7 Hz, 3/2 H), 0.79 (t, 7 Hz, 3/2 H). 10 FAB-MS: 601.2 (M+l).
Step A:
25
To a solution of the intermediate prepared in Example B62, Step C (235 mg) in methanol (3 ml) was added 1 N hydrochloric acid (0.5 ml) and stirred for an hour. To the resulting mixture was added NaCNBH3 (1.0 N in THF, 0.7 ml) and after 5 minūtes the reaction mixture was poured into 1 N hydrochloric acid and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and -247- LV 11525 concentrated. The residue was purified (chromatatron, hexanes/ethyl acetate=l/l) to give the desired product (142 mg).
Step B:
H HCI I Et02C
To a solution of the intermediate prepared in Step A (142 mg) in methanol was added HCI in ether and Pd(OH)2 and stirred under an hydrogen atmosphere for 12 hours. The mixture was filtered through Celite and the filtrate was concentrated to give the desired product (105 mg).
To the intermediate (105 mg) prepared in Step B in 2 ml of chloroform was added Intermediate 1 (81 mg), EDC (54 mg), HOBt (28 mg) and triethylamine (53 ml) and the reaction was stirred at room temperature for 12 hours and poured into water. The mixture was extracted with methylene chloride, dried over sodium sulfate and concentrated. Purification of the residue (chromatatron, hexanes/ethyl acetate=l/l) gavē the desired product which was treated with HCI in EtOAc to give the desired product (56 mg). 5 -248 - FAB-MS: 519.2 (M+l) 10
Step A: 15 EXAMPLE B73 (cis. dl+d2)
20
To the intermediate prepared in Example B72, Step A (100 mg) at 0°C in acetone was added Jones reaģent (4 N, 0.2 ml). After stirring for 16 hours in room temperature the mixture was quenched with 25 isopropanol, filtered through celite. The filtrate was extracted with ethyl acetate. The organics were washed with brine and dried over sodium sulfate and concentrated to give the desired product (100 mg).
Step B:
CBZ Et02C
30 -249- LV 11525
To the intermediate prepared in Step A (50 mg) in ether at 0°C was added diazomethane (Blati, Org. Syn. Collective Vol. 4, p225). The mixture was slowly warmed up to room temperature and stirred for 12 hours. Concentration and purification of the residue (PLC, hexanes/ethyl acetate=3/l) gavē the desired product (50 mg).
The intermediate prepared in Step B (50 mg) was dissolved in methanol and hydrogenated over Pd(OH)2/C at one atmosphere for one and half hours. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. To the residue in chloroform was added intermediate 1 (48 mg), EDC (45 mg) and HOBt (24 mg). After a couple of hours, the mixture was concentrated and purifīed (chromatatron, hexanes/ethyl acetate=l/l) to give the coupled product. Deprotection of this material by the HCl/EtOAc protocol gavē the desired product (47 mg). FAB-MS: 563.1 (M+l) -250- EXAMPLE B74 (cis. dl+d21
Step A:
CBZ I
VN'^S'C02Et H
To the intermediate prepared in Example B73, Step A (50 mg) in chloroform was added glycine ethyl ester HC1 salt (51 mg), EDC (46 mg) triethylamine (84 ml), and HOBt (32 mg). The reaction was stirred at room temperature for 12 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate, concentrated and purifīed (PLC, hexanes/ethyl acetate=l/l) to give the coupled product (45 mg).
Step B:
-251 - LV 11525
The tītie product (43 mg) was prepared from the intermediate (45 mg) obtained in Step A by the procedure desired in Example B73, Step C. FAB-MS: 634.2 (M+l). EXAMPLE B75 icis, dl+d2)
Step A:
CBZ i
To intermediate prepared in Example B73, Step A (53 mg) in chloroform was added ethanolamine (12 ml), EDC (37 mg) and HOBt (19 mg) and stirred at room temperature for 12 hours and poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate and concentrated. The residue was purified (chromatatron, methylene chloride/methanol=20/l) to give the coupled product (29 mg).
Step B: -252-
io The desired product (16.8 mg) was prepared from the above intermediate (29 mg) by the procedure described in Example B62, Steps F and G. FAB-MS: 581.2 (M+l). 15 EXAMPLE B76
25 To a solution of the intermediate prepared in Example B12,
Step A-l (100 mg) in acetic acid was added PtC>2 and hydrogenated at one atmosphere for 24 hours (monitored by TLC). The mixture was filtered through Celite, the filtrate was concentrated and the residue was azeotroped with toluene. The residue was dissolved in TFA and stirred 30 for 20 minūtes at room temperature. The reaction mixt *. was concentrated and the residue was dissolved in methylen^ chloride (0.5 ml) and was reacted with intermediate 1 (15 mg), EDC (15 mg), HOBt (6 mg) and triethylamine (11 ml). The mixture was stirred at room temperature for 3 hours and poured into water. The mixture was extracted with methylene chloride, dried over sodium sulfate and -253 - LV 11525 concentrated. Purification of the residue (PLC, hexanes/ethyl acetate=l/l) gavē the coupled product which was treated with HC1 in EtOAc to yield the desired product (8 mg). FAB-MS: 511.1 (M+l) ΕΧΑΜΡϋΕ B77 icis. dl+d2)
The intermediate prepared in Example B12, Step B was dissolved in methanol and hydrogenated over Pd(OH)2 at one atmosphere for a couple of hours. The mixture was filtered through celite and the filtrate was concentrated under vacuum. To the residue (88 mg) in chloroform (1 ml) was added N-Boc-P,P-dimethyl-p-alanine (48 mg, W.R. Schoen etc., J. Med. Chem.. 37, 897 (1994)), EDC (48 mg), and HOBt (30 mg), stirred for 12 hours and the mixture was poured into water. The mixture was extracted with methylene chloride, dried over sodium sulfate and concentrated. Purification of the residue (chromatatron, hexanes/ethyl acetate=l/l) gavē the coupled product that was deblocked with HC1 in EtOAc to give the desired product (58 mg). FAB-MS: 519.2 (M+l) -254- EXAMPLE B78 (cis. dl+d21
o
To a solution of methyl (R)-lactate (1 ml) in dihydropyran (5 ml) was added one drop of concentrated hydrochloric acid at room temperature. The reaction was stirred for an hour, concentrated and purified by chromatatron (hexanf*s/ethyl acetate=3/l) to give the desired product (1.49 g). To the THP piotected lactate (500 mg) in toluene (10 ml) vvas added diisobutylaluminum hydride (IN in cyclohexane, 3.45 ml) at -78°C and after one and half hours, the reaction was quenched with methanol at low temperature. The mixture was poured into 5% aqueous citric acid and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the protected aldehyde. -255- LV 11525
Step B:
To a solution of the product (25 mg) prepared in Example B77 in methanol (0.5 ml) was added the intermediate (36 mg) prepared in Step A and sodium acetate (18 mg) and stirred at room temperature for an hour. To the mixture was added NaCNBH3 (IN in THF, 90 ml) slowly and stirred for 16 hours and concentrated. The residue was purified by chromatatron (methylene chloride/methanol/ammonium hydroxide=10/l/0.1) to give the desired product which was dissolved in methanol (0.5 ml) and was treated with 9 N hydrochloric acid (0.2 ml). After stirring for 2 hours, the mixture was concentrated and dried to give the desired product (10.5 mg). FAB-MS: 577.4 (M+l). -256- EXAMPLE C1
Step A: OEt
O
To a stirred solution of ethyl nipecotate (15 g, 95.4 mmol) and DMAP (0.05 eq.) in dichloromethane at 0°C was added dropwise by an addition funnel di-tert-butyl dicarbonate (21.8 g, 100 mmol) in dichloromethane (200 mL). The mixture was stirred for 2-3 hours. The solution was vvashed with 3 N HC1 and saturated sodium chloride, dried over anhydrous magnesium sulfate; then filtered and concentrated to give the desired product (18.7 g, 88%).
Step B:
Boc
-257- -257- LV 11525
To a stirred solution of ethyl N-t-Boc nipecotate (7 g, 26.90 mmol) in THF (100 mL) at -78°C under argon was added LHMDS (28 mL, 28 mmol) over a 10 minūte period. The solution was allowed to stir an additional 30 minūtes at -78°C; then benzyl bromide (4.8 g, 28 mmol) was added slowly to the solution. The reaction mixture was stirred ovemight and allowed to warm to room temperature. The material was concentrated, then diluted with vvater, and extracted using ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography, eluting with 20% ethyl acetate in hexane, provided the title compound. (8.32 g, 88%). FAB-MS calc. for C20H29NO4: 347; Found 348 (M+H)
Step C:
A solution of the intermediate from Step B (8 g, 23.02 mmol) in ethyl acetate (80 mL) was cooled to 0°C. While stirring, hydrogen chloride gas was bubbled into the mixture until saturation occurred. The reaction was stirred for 40 minūtes, until TLC analysis indicated that the reaction was complete. The solution was then concentrated to remove the ethyl acetate to afford the product (6.53 g, 99%). 1H NMR (CDCI3,400MHz) δ 7.25-7.19 (m, 3 H), 7.04-7.01 (m, 2 H), 5.35 (v. br. s, 2 H), 4.22-4.10 (m, 2 H), 3.44 (d, J = 13 Hz, 1 H), 3.21 (br. d, J = 12.7 Hz, 1 H), 2.95 (d, J = 13.5 Hz, 1 H), 2.76-2.68 (m, 3 H), 2.22 (br. d, J — 13 Hz, 1 H), 1.73-1.71 (m, 1 H), 1.61-1.48 (m, 2 H), 1.18 (t, J = 7 Hz, 3 H). FAB-MS calc. for C15H21NO2: 247; Found 248 (M+H) -258-
Step D:
To a solution of the intermediate prepared in the previous step (1.2 g, 4.23 mmol), and Intennedate 1 (1 eq.), HOBT (1 eq.), and N-15 methyl morpholine (1 eq.) in dichloromethane cooled to 0°C was added EDC(1.5eq.). The reaction mixture was stirred at 0°C ovemight. The solution was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate; then filtered and concentrated. Purification by MPLC eluting with 40% ethyl acetate in hexane provided 20 two enantiomerically pure compounds. The compound which came out first from the column was designated as dl (1.14g), which has an R-absolute stereochemistiy at the 3-position of the nipecotate; and the compound which came out of the column second was designated as d2 (1.08 g), which has an S-absolute stereochemistry (see Example C2 for 25 assignment) at the 3-position of the nipecotate. dl FAB-MS calc. for C35H46N4O6: 618; Found 619 (M+H) d2 FAB-MS calc. for C35H46N4O6: 618; Found 619 (M+H)
Step E: 30 -259- LV 11525
Prepared by the procedure described in Step C from the intermediates dl from the previous step (1 g) in ethyl acetate (20 mL) and HC1 gas at 0°C for 1.5 hours. Product: 860 mg, 91%. FAB-MS calc. for C30H38N4O4: 518; Found 519 (M+H)
EXAMPLE C1A
Prepared by the procedure described in Step C of Example C1 from 1 g of the d2 intermediates from the Step D of Example C1 in ethyl acetate (20 mL) by bubbling HC1 at 0°C until saturated and then evaporated after 30 minūtes to give the title compound (878 mg, 93%). FAB-MS calc. for C30H38N4O4: 518; Found 519 (M+H) lH NMR (CD3OD, 400MHz) compound exists in two rotamers in approximately a 5/3 ratio that slowly interconvert relative to the NMR time scale δ 7.60 (d, J = 7.9 Hz, 5/8 H), 7.55 (d, J = 7.9 Hz, 3/8 H), 7.34-6.93 (m, 9H), 5.36 (dd, J = 5.2Hz, 9.7 Hz, 3/8 H), 5.31 (dd, J = 6.7 Hz, -260- 8.8 Hz, 5/8 Η), 4.23 (br. d, J = 13.7 Hz, 3/8 H), 4.10-4.00 (m, 6/8 H), 4.04-3.98 (m, 3/8 H), 3.96-3.82 (m, 10/8 H), 3.80 (br. d, J = 13.5 Hz, 5/8 H), 3.36 (br. d, J = 13.3 Hz, 5/8 H), 3.29-3.22, 3.17-3.10, (2m, 2H), 3.20 (br. d, J = 14.5 Hz, 3/8 H), 3.10-2.96 (m, 5/8 H), 2.90 (s, 6/8 H), 2.60 (d, J = 13.4 Hz, 5/8), 2.41 (d, J = 13.4 Hz, 5/8 H), 2.19-2.12, 1.82-1.70, 1.68-1.60, 1.50-1.40, 1.34-1.25, 1.05-0.95 (6m, 4 H),1.55 (s, 9/8 H), 1.50 (s, 15/8 H), 1.09 (t, J = 7.1 Hz, 3 H).
The additional intermediates shown in Table CI were prepared according to the above established procedures as exemplified in Example C1 steps A through C. The fīnal compounds were prepared according to Example C1 Steps D and E, and Example CIa using Intermediate 1.
TABLE CI: ADDITIONAL EXAMPLES
Intermediate Product Intermediate Product entry Y MF MF FAB-MS (M+l) FAB-MS (M+l) isomera 1 Me C9H17NO2 C24H34N4O4 , 443 dl 171 (M+, EI-MS) d2 2 Et C10H19NO2 C25H36N4O4 dl 185 (M+, EI-MS) d2 3 n-Pr Ci 1H21NO2 C26H38N4O4 dl 199 (M+,EI-MS) d2 -261 - LV 11525 allyl C11H19NO2 C26H36N4O4 469 dl 198 d2 n-Bu C12H23NO2 C27H40N4O4 485 dl 213 (M+EI-MS) d2 -CH20Et C11H21NO3 216 C26H38N4O5 487 RS cyclohexane- C15H27NO2 C30H44N4O4 525 dl methyl 254 d2 Ph(CH2)2- C16H23N02 C31H40N4O4 533 dl 261 (M+EI-MS) d2 Ph(CH2)3- C17H25NO2 C39H4?N404 547 dl 275 (M+EI-MS) d2 o-MeOBn- CI6H23NO3 C31H40N4O5 549 dl 278 d2 m-MeOBn- CI6H23NO3 C31H40N4O5 549 dl 278 d2 p-MeOBn- CI6H23NO3 C31H40N4O5 549 dl 278 d2 o-Me-Bn- C16H23N02 C31H40N4O4 533 dl 262 d2 m-Me-Bn- C16H23N02 C31H40N4O4 533 dl 262 d2 p-Me-Bn- C16H23NO2 C31H40N4O4 533 dl 262 d2 o-Cl-Bn- C15H20NO2CI C30H37N4O4CI dl 282,284 (3:1) 554,556 (3:1) d2 m-Cl-Bn- C15H20NO2C1 C30H37N4O4CI dl 282,284 (3:1) 554,556 (3:1) d2 p-Cl-Bn- C15H20NO2CI C30H37N4O4CI dl 282,284 (3:1) 554,556 (3:1) d2 2,6-di-Cl-Bn- C15H19NO2CI2 C30H36N4O4CI2 316,318,320 587,589,591 p-Br-Bn- Cl5H20NO2Br C30H37N4O4Br dl 326,328 (1:1) 597,599(1:1) d2 -262- 18 m-Br-Bn- Ci5H2QN02Br C30H37N4O4Br dl 326,328 (1:1) 597,599 (1:1) d2 19 o-nitro-Bn- C15H20N2O4 C30H37N5O6 dl 293 564 d2 20 m-nitro-Bn- C15H20N2O4 C30H37N5O6 dl 293 564 d2 21 p-nitro-Bn- C15H20N2O4 C30H37N5O6 dl 293 564 d2 22 l-naphthylmethyl C19H23NO2 C34H40N4O4 dl 298 569 d2 23 jTļ C13H18N02SC1 Cl^g^CHa- 288,290(3:1) C28H35N4O4SCI dl 559,561(3:1) d2 24 Bn02C- C16H21NO4 C31H38N4O6 RS 292 563 25 Et02C- C11H19NO4 C26H36N4O6 RS 230 501 26 p-Ph-Bn- C21H25NO4 C36H42N4O4 dl 324 595 d2 27 0 C16H20NO4C1 C31H37N4O6CI dl 1 1 326,328(3:1) Cl 597, 599(3:1) d2 28 9 C17H20N2O4 C32H37N5O6 dl 1 | N-CH2- 317 588 d2 Ο a: In this and in subsequent tables for isomer designation: R or S means the stereochemistry at the carbon atom to which X and Y are attached, RS means it is a mixture of the two isomers at this center; dl or d2 means the two diastereomers were separated and are as defined in Example C1 step D.
The additional examples shown in Table CIa were prepared according to Example C1 Steps D and E, using Intermediate 1 and commercially available intermediates. -263- LV 11525
TABLE CIa: ADDITIONAL EXAMPLES
Intermediate Product Product entry X MF FAB-MS (M+l) isomer 1 -OH C20H28N4O3 373 RS 2 -CH20H C21H30N4O3 387 RS 3 -C02Et C23H32N4O4 429 RS 4 C02Bn C28H34N4O4 491 RS 5 CONMe2 C23H33N5O3 428 RS
The additional Products shown in Table CIb vvere prepared according to Example C1 Steps D and E, using Intermediate 3 and some of the intermediates shown in Table Cl. -264-
TABLE CIb: ADDĪTIONAL EXAMPLES
Product entry Y MF FAB-MS (M+l) isomer 1 Bn C30H41N3O4 508 R 9 Bn C30H41N3O4 S 508 3 Ph(CH2)2 C31H43N304 522 dl d2 4 Ph(CH2)3 C32H45N3O4 536 dl d2 5 l-naphthylmethyl C34H43N3O4 558 RS 6 Cr%^CH2- C28H38N3O4SCI 548,550 (3:1) RS 7 p-Ph-Bn- C36H45N3O4 584 RS 8 Bn02C- C31H41N3O6 552 RS 9 C31H40N3O6C1 dl 586,588 (3:1) d2
The additional products shown in Table CIc were prepared according to Example C1 Steps D and E, using Intermediate 2 and some of the intermediates shown in Table CI. -265 - LV 11525
TABLE CIc: ADDITIONAL EXAMPLES
entry Y MF FAB-MS (M+l) īsomer 1 Bn C29H39N305 510 R 2 Bn C29H39N305 510 S 3 Et C24H37N305 448 RS 4 Ph(CH2)2 C30H41N3O5 524 dl d2 5 Ph(CH2)3 C31H43N305 538 dl d2 6 H C22H33N305 420 RS ΕΧΑΜΡΕΕ C2
Step A: -266- H L-tartaric acid
N
0 OEt
The intermediate from Example Cl, Step C (50.8 g) was dissolved in dichloromethane and it was washed with 3N NaOH. The aqueous layer was extracted with dichloromethane and the combined solution was dried (MgS04) and evaporated to give the free amine as an oil. The ethyl 3-benzyl nipecotate and D-tartaric acid (31 g) were c ->lved in 880 mL of water/acetone (1:4) solution with heating. The so.ution was left in the refrigerator ovemight and the crystals which were formed were filtered off. Recrystallization in 470 mL of water/acetone (1:4) at room temperature gavē the ethyl 3-(R)-benzyl nipecotate D-tartaric acid salt (21 g).
The structure of this compound was determined by X-Ray crysiallographic analysis. With the configuration of D-tartaric acid knovvn to be S,S, the configuration of the chiral site in this ethyl 3-benzylmipecotate salt was determined to be R.
The combined mother liquor was evaporated and to it was added 3N NaOH and dichloromethane, the mixture was stirred for 30 minūtes and the organic layer was separated. The aqueous was extracted twice with dichloromethane and the combined organic extracts were dried over MgS04 and evaporated to give 24.4 g of the S-isomer enriched compound. It was crystallized with L-tartaric acid (14.8 g) in 400 mL of water/acetone (1:4) at room temperature to give ethyl 3 (S)-benzyl nipecotate L-tartaric acid salt (27.3 g). 1H NMR (CD3OD, 400MHz) δ 7.31-7.22 (m, 3 H), 7.12-7.09 (m, 2 H), 4.40 (s, 2 H, from tartaric acid), 4.30-4.10 (m, 2 H), 3.49 (br. d, J = 13 Hz, 1 H), 3.06 (d, J = 13.6 Hz, 1 H), 2.98 (d, J = 13 Hz, 1 H), 2.92 (dt, J = 3.3 Hz, 13 Hz, 1 H), 2.82 ( d, J = 13.6 Hz, 1 H), 2.30 (d, J = 12.4 Hz, 1 -267- LV 11525 H), 1.88 (td, J = 3 Hz, 14.5 Hz, 1 H), 1.69 (dt, J = 3 Hz, 13 Hz, 1 H), 1.63-1.51 (m, 1 H), 1.25b (q, J = 7.1 Hz, 3 H).
Step B:
Ethyl 3 (S)-benzyl nipecotate L-tartaric acid salt (39.74 g) was suspended in 70 mL of 3N NaOH and 70 mL of water, follovved by extraction with dichloromethane. The extracts were combined, dried, and evaporated to give a thick oil. To a stirred solution of the oil, N-t-Boc D-TrpOH (30.43 g) and HOBt (13.5 g) in dichloromethane (200 mL) at 0°C, was added EDC (23 g) in several portions. The mixture was stirred ovemight and it was poured into water and 3 N HC1 and was extracted with dichloromethane. The organic layer vvas washed with brine, saturated sodium bicarbonate, dried over MgS04 and evaporated to give a crude product (67.7 g), which was used without further purification. FAB-MS calc. for C31H39N3O5: 533; Found 534 (M+H)
Step C:
-268-
To a solution of the intermediate from the previous step (67.7 g crude) in ethyl acetate (100 mL) at 0°C, was bubbled HC1 gas until it was saturated. The reaction mixture was stirred at 0°C for 30 minūtes and was evaporated to remove excess HC1 and ethyl acetate. The residue was suspended in dichloromethane and was washed with a mixture of 3 N NaOH (70 mL) and water (100 mL). The organic layer was dried (MgS04), evaporated to a small volume and used in next step vvithout further purification. FAB-MS calc. for C26H31N3O3: 433; Found 434 (M+H)
Step D:
A solution containing the intermediate obtained in the last step, N-Boc-a-Me-AlaOH (20.3 g), and DMAP (200 mg) in dichloromethane (100 mL) was stirred at room temperature and to it was added EDC (24 g) in several portions. The reaction mixture was stirred for 3 hours and was worked up by diluting it with dichloromethane and washing with 3 N HC1, brine, and saturated sodium bicarbonate solution. The organic layer was dried over MgS04, and evaporated to give a thick oil. This oil was passed through a pad of silica gel, eluting with 60% ethyl acetate in hexane to remove some very polar impurities, to give the desired compound (54.2 g) FAB-MS calc. for C35H46N4O6: 618; Found 619 (M+H)
Step F: -269- LV 11525
To a solution of the intermediate from the previous step (54.2 g) in ethyl acetate (100 mL) at 0°C, was bubbled HC1 gas until it was saturated. The reaction mixture was stirred at 0°C for 15 minūtes and was evaporated to remove excess HC1 and ethyl acetate. The residue was first dissolved in dichloromethane (100 mL) and then ethyl acetate (300 mL) was added. The mixture was stirred ovemight and the solid was collected by flltration to give the title compound (34 g). Further evaporation of the mother liquor to a small volume gavē the second crop of product (10.1 g). MS and NMR identical with Example C1A.
The additional products shown in Table CII were prepared according to Example C2, Steps B through F, using the readily available Boc protected amino acids instead of N-t-Boc-D-TrpOH.
TABLE CII
Product -270- entry R MF FAB-MS (M+l) 1 4-F C30H37N4O4F 537 2 5-F C30H37N4O4F 537 3 6-F C30H37N4O4F 537 4 1-Me C31H40N4O4 533 5 5-MeO C31H40N4O5 549 6 5-HO C30H38N4O5 535 7 6-MeO C31H40N4O5 549 EXAMPLE C3
Step A:
Boc čx C02Et
To a stirred solution of ethyl 3-pyrrolidinecarboxylate hydrochloride (J. Chem. Soc., 24,1618-1619; 10 g, 69.8 mmol), triethylamine (7.75 mL) and DMAP (857 mg) in dichloromethane (40 mL), was slowly added di-t-butyl dicarboxylate (18.3 g, 83.7 mmol) and -271 - LV 11525 the resulting mixture was stirred at room temperature for three days. The mixture was then concentrated, washed with 3 N HC1 and dried and evaporated to give the intermediate.
Step B:
Boc C02Et
Prepared by the procedure described in Example Cl, Step B from the intermediate obtained from previous step (500 mg, 2.05 mmol), KHMDS (5.12 mg, 2.57 mmol) and benzyl bromide (371 mg, 2.16 mmol). Purifīcation by silica gel flash column eluting with 5-20% ethyl acetate in hexane provided the title compound (385 mg, 56%).
Step C:
H HCI
C02Et
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (385 mg, 1.16 mmol) in ethyl acetate (5 mL) and HCI gas at 0°C for 15 minūtes (306 mg, 98%). -272-
Step D:
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (138 mg, 0.514 mmol), intermediate 1 (200 mg, 0.514 mmol), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (2 eq.). Purification by MPLC, eluting with 60% ethyl ačetate in hexane gavē the product (250 mg, 80%) 15 FAB-MS calc. for C34H44N4O6: 604; Found 605 (M+H).
Step E:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (250 mg, 0.036 mmol) in ethyl acetate (3 mL) and HC1 gas at 0°C for 10 minūtes. FAB-MS calc. for C29H36N4O4: 504; Found 505 (M+H). 30 -273- LV 11525 EX AMPLE C4
To a stirred solution of ethyl N-t-Boc nipecotate (4 g, 15.7 mmol)) in THF (100 mL) at -78°C under argon was added LHMDS (1 M, 32 mL, 32 mmol) over a 10 minūte period. The solution was allowed to stir an additional 30 minūtes at -78°C; then methyl disulfide (1.92 g, 20.37 mmol) was added slowly to the solution. The reaction mixture was stirred ovemight and allowed to warm to room temperature. The material was concentrated, then diluted with water, and extracted using ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography eluting with 20% ethyl acetate in hexane provided the title compound. FAB-MS calc. for C14H25NO4S: 271; Found 272 (M+H)
Step B:
HHCI
O OEt
-274-
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (1 g, 3.3 mmol) in ethyl acetate (25 mL) and HC1 gas at 0°C for 35 minūtes to yield the product (783 mg, 99%). FAB-MS calc. for C9H17NO2S: 171; Found271 (M+H)
Step C: 10 15
20 25
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (123 mg, 0.514 mmol), Intermediate 1 (1 eq.), HOBT (1 eq.), NMM (1 eq.), and EDC (197 mg, 1.028 mmol). Purifīcation by MPLC provided diastereomers. The compound which came out first from the column was designated as dl (109 mg, 37%); and the compound which came out of the column second was designated as d2 (88 mg, 30%), dl FAB-MS calc. for C29H42N4O6S: 574; Found 575 (M+H) d2 FAB-MS calc. for C29H42N4O6S: 574; Found 575 (M+H)
Step D:
30 -275 - LV 11525
Prepared by the procedure described in Example Cl, Step C from the intermediates dl(80 mg) and d2 (80 mg) separately from the previous step in ethyl acetate (5 mL each) and HC1 gas at 0°C for 20 minūtes. 5 dl: (71 mg, 99%) d2: (70 mg, 98%) dl lH NMR (CD3OD, 400MHz): The compound exists in two rotamers in approximately a 1:1 ratio. δ 7.71 (d, J = 7.2 Hz, 1/2 H), 7.56 (d, J = 7.2 Hz, 1/2 H), 7.38 (d, J = 8.0 Hz, 1/2 H), 7.33 (d, J = 7.5 Hz, 1/2 H), 10 7.14-7.01 (m, 3 H), 5.44 (dd, J = 6 Hz, 8 Hz, 1/2 H), 4.30-4.10 (m, 5/2 H), 3.92 (d, J = 13.3 Hz, 1/2 H), 3.81 (d, J = 13.3 Hz, 1/2 H), 3.67 (d, J = 13.3 Hz, 1/2 H), 3.48-3.40 (m, 1/2 H), 3.28-3.09 (m, 7/2 H), 2.55 (dt, 1/2 H), 2.26-2.20 (br. d, 1/2 H), 2.05 (s, 3 H), 1.80-1.70 (m, 1/2 H), 1.67, 1.59, 1.55, 1.43 (4s, 6 H), 1.27 (t, J = 7.0 Hz, 3/2 H), 1.19 (t, J = 7.0 Hz, 15 3/2 H), 0.90-0.85 (m, 1/2 H). d2 lH NMR (CD3OD, 400MHz): The compound exists in two rotamers in approximately a 1:1 ratio. δ 7.77 (d, J = 7.5 Hz, 1/2 H), 7.56 (d, J = 7.9 Hz, 1/2 H), 7.35-7.30 (m, 1 H), 7.13-6.98 (m, 3 H), 5.53 (dd, J = 5.5 20 Hz, 8 Hz, 1/2 H), 5.24 (app. t, J = 7 Hz, 1/2 H), 4.30 (br. d, J = 14 Hz, 1/2 H), 4.20-4.10 (m, 2 H), 3.90-3.85 (m, 1/2 H), 3.86 (d, J = 13.2 Hz, 1/2 H), 3.70 (d, J = 13.7 Hz, 1/2 H), 3.35-3.10 (m, 4 H), 2.30-2.20 (m, 1/2 H), 2.12, 2.04 (2s, 3 H), 2.04-2.00 (m, 1/2 H), 1.80-1.70 (m, 3/2 H), 1.54, 1.50, 1.43, 1.26 (4s, 6 H), 1.23 (t, J = 6.7 Hz, 3 H), 0.90-0.84 (m, 1/2 H). 25 dl FAB-MS calc. for C24H34N4O4S: 474; Found 475 (M+H) d2 FAB-MS calc. for C24H34N4O4S: 474; Found 475 (M+H)
The additional intermediates shovvn in Table Cili were prepared according to the above established procedure as exemplified in 3 0
Example C4 steps A and B. The final compounds were prepared according to Example C4 Steps C and D, using Intermediate 1. -276-
C02Et Intermediate TABLE Cili
10 entry Y
Intermediate MF FAB-MS (M+l)
Product MF FAB-MS (M+l) īsomer 15 1 2 3 4
PhS- BnS- 2-pyridylthio- C14H19NO2S 266 C15H21N02S 280 C13H18N202S 267 -S-< N. C29H36N4O4S dl 537 d2 C30H38N4O4S dl 551 d2 C28H35N5O4S RS 538 C27H35N5O4S2 RS 558 20 EXAMPLE C5 25
30 -277- 5
Step A:
0 OEt LV 11525
To a stirred solution of NaI04 (316.5 mg, 1.48 mmol) in water (5 mL) and ethanol (5 mL) was added the intennediate from Example C4, Step A (300 mg, 0.99 mmol). The mixture was stirred for 5 hours at room temperature, then concentrated to remove ethanol. The material was then extracted with ethyl acetate (2x10 mL). The organic layer was dried over magnesium sulfate and concentrated to give the title compound (286 mg, 90.5%). FAB-MS calc. for C14H25NO5S: 319; Found 320 (M+H)
Step B: 20
H HCI
o 25
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (230 g, 0.72 mmol) in ethyl acetate (10 mL) and HC1 gas at 0°C for 25 minūtes (197 mg, 100%). FAB-MS calc. for C9H17NO3S: 219; Found 220 (M+H) 30 -278-
Step C:
10
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (140 mg, 0.547 mmol), Intermediate 1 (1 eq.), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (210 mg, 1.094 mmol). Purifīcation by MPLC provided a 15 diastereomeric mixture of compounds (177 mg, 55%). FAB-MS calc. for C29H42N4O7S: 590; Found 591 (M+H)
Step D:
Prepared by the procedure described in Example Cl, Step C 30 from the intermediate from the previous step (150 mg, 0.254 mmol) in ethyl acetate (10 mL) and HC1 gas at 0°C for 20 minūtes (118 mg, 90%). FAB-MS calc. for C24H34N4O5S: 490; Found 491 (M+H) -279- LV 11525 EXAMPLE C6
Step A:
Boc Nv
-OEt
To a stirred solution of Oxone (910 mg, 1.48 mmol) in water (5 mL) and methanol (5 mL) was added the intermediate from Example C4, Step A (300 mg, 0.99 mmol). The mixture vvas stirred for 4 hours at room temperature, then concentrated to remove methanol. The residue was then extracted with ethyl acetate (2x10 mL). The organic layer was dried over magnesium sulfate and concentrated to give the title compound (321 mg, 97%). FAB-MS calc. for C14H25NO6S: 335; Found 336 (M+H) [Found 236 (M- t-Boc)]
Step B:
HHCI
.OEt -280-
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (221 mg, 0.66 mmol) in ethyl acetate (10 mL) and HC1 gas at 0°C for 25 minūtes (192 mg, 99%). FAB-MS calc. for C9H17NO4S: 235; Found 236 (M+H)
Step C: 10 15
20
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (140 mg, 0.515 mmol), Intermediate 1 (1 eq.), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (197 mg, 1.03 mmol.). Purification by MPLC provided a diastereomeric mixture of compounds (251 mg, 80%). FAB-MS calc. for C29H42N4O8S: 606; Found 607 (M+H)
Step D:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (210 mg, 0.317 mmol) in -281 - LV 11525 ethyl acetate (10 mL) and HC1 gas at 0°C for 30 minūtes (193 mg, 98.5%) FAB-MS calc. for C24H34N4O8S: 506; Found 507 (M+H) EXAMPLE C7
Step A:
Boc
.OEt
To a stirred solution of ethyl N-t-Boc nipecotate (50 g, 0.196 mol) in THF (600 mL) at -78°C under argon was added KHMDS (0.5 M in toluene, 298 mL, 0.298 mol) over a 30 minūte period. The solution was allovved to stir an additional 30 minūtes at -78°C. Meanwhile, a suspension of 2-picolyl chloride hydrochloride (25 g) in dichloromethane was washed with a mixture of 3 N NaOH and brine to remove the hydrochloride. The organic layer was dried over MgS04 and evaporated to yield a brown oil and it was added slowly to the solution at -78°C.
The reaction mixture was stirred ovemight and allowed to warm to room temperature. The material was concentrated, then diluted with water, and extracted using ethyl acetate. The organic layer was dried over -282- anhydrous magnesium sulfate, flltered, and concentrated. Purification by silica gel flash column chromatography eluting with a solvent gradient of 20-80% ethyl acetate in hexane provided the title compound. (54.8 g, 80%).lH NMR (CD3OD, 400MHz) δ 8.45 (dd, J = 1.5 Hz, 5 Hz, 1 H), 5 7.52 (app dt, J = 2 Hz, 8 Hz, 1 H), 7.07 (dd, J = 5 Hz, 6.6 Hz, 1 H), 7.05 (d, J = 8 Hz, 1 H), 4.09-4.04 (br. m, 2 H), 3.92 (br. d, 1 H), 3.46 (br. m, 1 H), 3.30-3.10 (br. m, 1 H), 3.06 (d, J = 13.7 Hz, 1 H), 2.95 (d, J = 13. 7 Hz, 1 H), 2.01-1.91 (br. m, 1 H), 1.63-1.50 (br. m, 3 H), 1.36 (v. br. s, 9 H), 1.13 (t, 7.1 Hz, 3 H). FAB-MS calc. for C19H28N2O4: 348; Found 10 349 (M+H)
Step B:
H HCI N
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (6.36g, 18.2 mmol) in ethyl acetate (100 mL) and HCI at 0°C for 45 minūtes (6.10g, 100%.) FAB-MS calc. for C14H20N2O2: 248; Found 249 (M+H) 25 Step C:
O -283- LV 11525
Prepared by the procedure described in Example Cl, Step D from the compound prepared in the previous step (500 mg, 1.556 mmol), Intermediate 1(1 eq.), HOBT (1 eq.), N-methyl morpholine (2 eq.), and EDC (597 mg, 3.11 mmol). Purification by MPLC eluting with ethyl acetate provided the title compound (883 mg, 91.5%). FAB-MS calc. for C34H45N5O6: 619; Found 620 (M+H)
Step D:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (250 mg, 0.404 mmol) in ethyl acetate (25 mL) and HC1 gas at 0°C for 25 minūtes (204 mg, 85%) FAB-MS calc. for C29H37N5O4: 519; Found 520 (M+H)
The additional intermediates shown in Table CIV vvere prepared according to the above established procedure as exemplified in Example C7 step A and B. The final compounds were prepared according to Example C7 Steps C and D, using Intermediate 1.
Intermediate
TABLE CIV
Product -284- īsomer entry Υ
Intermediate Product
MF MF FAB-MS (M+l) FAB-MS (M+l) 10 15 1 3-picolyl C14H20N202 C29H37N504 RS 249 520 2 4-picolyl C14H20N2O2 C29H37N504 RS 249 520 3 2-quinoline- C18H22N202 C33H39N504 RS methyl 298 569 4 Q>ch2. C16H21N302 C31H38N604 dl 288 559 d2 5 n Bn CH2" C19H25N3O2 328 C34H42N604 599 RS 6 C15H22N2O2 C30H39N5O4 RS 263 534
N CHo- 20
The additional compounds shown in Table CIVa were prepared according to Example C7 Steps C and D, using some of the intermediates shown in Table CIV and Intermediate 3 instead of Intermediate 1.
TABLE CIVa: ADDITIONAL EXAMPLES 25
entry Y
MF FAB-MS (M+l) īsomer 30 -285- LV 11525 1 2 3 4 2- picolyl 3- picolyl 4- picolyl 5 6
C31H41N504 548 C30H42N4O4 523,545(M+Na) C29H40N4O4 509 C29H40N4O4 509 C29H40N4O4 509 C33H42N404 559
dl d2 dl d2 dl d2 RS dl d2 dl d2 EXAMPLE Γ8
I I ļl J 1 C=0 O
NH2 HCI
OEt -286
Prepared by the procedure described in Example Cl, Step D from the intermediate (6g, 18.67 mmol) prepared in Example C7, Step B, and using (R)-(-)-(0)-acetyl mandelic acid (1 eq.), HOBT (1 eq.), N-methyl morpholine (2 eq.), and EDC (7.16 g, 37.34 mmol). Purification by MPLC eluting with 80% ethyl acetate in hexane provided two enantiomerically pure compounds. The isomer which came out of the column first was designated as dl (3.92 g, 99%) and the isomer which came out of the column second as d2 (3.69 g, 93%) FAB-MS calc. for C24H28N2O5 Found 425. The structure of intermediate dl was determined by x-ray crystallography. Given the absolute stereochemistry of (R) -O- acetylmandelic acid, the stereochemistry at the piperidine 3-position was assigned (S)- in dļ.
Step B:
H HCI
OEt
The intermediate dl from the previous step (2.91g, 6.86 mmol) in ethanol (30 mL) and concentrated HCI (25 mL) was refluxed for five hours. The reaction mixture was evaporated in vacuo and the -287- LV 11525 residue was purified by silica gel flash column chromatography eluting with a solvent gradient of 1:10:90 to 2:20:80 ammonium hydroxide:methanol:chloroform to provide the compound (dl, 1.52g, 70%). lH NMR (CD3OD, 400MHz) δ 8.84 (app. d, J = 6 Hz, 1 H), 8.60 5 (app. dt, J = 1.5 Hz, 8 Hz, 1 H), 8.04 (t, J = 6 Hz, 1 H), 7.94 (d, J = 8 Hz, 1 H), 4.34-4.27 (m, 1 H), 4.23-4.17 (m, 1 H), 3.75 (d, J = 13 Hz, 1 H), 3.46 (d, J = 13.3 Hz, 1 H), 3.40 (d, J = 13.3 Hz, 1 H), 3.31-3.29 (m, 2 H), 3.20 (d, J = 13 Hz, 1 H), 3.03 (app dt, J = 3.1 Hz, 12.8 Hz, 1 H), 2.24 (br. d, 1 H), 2.00-1.93 (m, 1 H), 1.88 (dd, J = 3.7 Hz, 13.5 Hz, 1 H), 1.63-1.60 10 (m, 1 H), 1.23 (t, 7.1 Hz, 3 H). FAB-MS calc. for C14H20N2O2: 248;
Found 249 (M+H)
Step C: 15 rr c=o NHBoc 20 N'
OEt ΊΓ 0
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in Step B of this example (dl, 1.50g, 4.67 mmol), N-t-Boc-D-Trp (1 eq.), HOBT (1 eq.), and EDC (1.53g, 8.00 mmol). Purifīcation by MPLC eluting with ethyl acetate provided the title compound (1.764 g, 71%). FAB-MS calc. for C30H38N4O5: 534; Found 535 (M+H) 30 5 -288- 10
Step D:
Prepared by the procedure described in Example C3, Step C from the intermediate from the previous step (1.658 g, 3.11 mmol) in ethyl acetate (50 mL) and HC1 gas at 0°C for 35 minūtes (1.56 g, 99%). FAB-MS calc. for C25H30N4O3:434; Found 435 (M+H)
Step E:
20 25
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in Step D of this example (1.5 g, 2.96 mmol), N-t-Boc-a-methylalanine (1.1 eq.) DMAP (0.15 eq.), N-methyl 30 morpholine (1 eq.), and EDC (1.135 g, 5.92 mmol). Purification by MPLC provided the title compound. (1.488g, 81%) FAB-MS calc. for C34H45N5O6: 619; Found 620 (M+H) -289- LV 11525
Step F:
Prepared by the procedure described in Example Cl, Step C from the intermediate from Step E (1.40 g, 2.26 mmol) in ethyl acetate (100 mL) and HC1 gas at 0°C for 1 hour (1.388 g, 100%). 15 1H NMR (CD3OD, 400 MHz):8.79-8.78 (Μ, 1H), 8.56-8.48 (M, 24), 8.0-7.96 (Μ, 1H), 7.72 (d, J=8.21 Hz, 1H) 7.53 (d, J=7.98, Hz, 1H) 7.25-7.22 (Μ, 2H) 6.89-6.86 (Μ, 1H) 5.48-5.43 (Μ, 1H) 3.89 (1, J=7.1 Hz, 2H) 2.30 (d, J=14.3 Hz, 1H) 1.85 (d, J=14.4 Hz, 1H) 1.01 (t, J=7.1 Hz, 3H) FAB-MS calc. for C29H37N5O4: 519; Found 520 (M+H) EXAMPLE C9
The title compound was similarly prepared from the intermediate d2 from Example C8, Step A. FAB-MS calc. for C29H37N5O4: 519; Found 520 (M+H) -290-
EXAMPLE CIO
Step A:
Boc
l\L
k ^OH
O
To a stirred solution of nipecotic acid (5 g, 38.7 mmol) in NaOH (2 eq.) in vvater was added di-tert-butyl dicarbonate (10 g, 46.44 mmol). The mixture was stirred at room temperature for 2 days. The mixture was then slowly acidified to pH=3 and stirred for two hours. The solution was extracted with ethyl acetate, dried, and concentrated to give white solid (6.25 g, 70%).
Step B:
Boc
l\L k .OBn
O
To a solution of the intermediate from the previous step (6.25 g, 27.3 mmol), benzyl alcohol (3.4 mL, 32.7 mmol) and DMAP (33 mg, 0.273 mmol) in dichloromethane at 0°C, was added EDC (6.9 g, 35.4 mmol). The reaction mixture was stirred at room temperature for 7 -291 - LV 11525 hours. It was washed with a mixture of brine and 3 N HC1, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel flash column eluting with a gradient of 10-30% ethyl acetate in hexane provided the benzyl ester (7.41 g,85%). 5
Step C:
Boc
Prepared by the procedure described in Example Cl, Step B 15 from benzyl N-t-Boc-nipecotate (7.12 g, 22.2 mmol), LHMDS in THF (33.3 mL, 33.3 mmol) and benzyl bromide (4.0 g, 33.3 mmol). Purification by silica gel flash column chromatography eluting with 5-20% ethyl acetate in hexane provided the title compound. (9.10 g, 100%) lH NMR (CDC13,400MHz) δ 7.33-7.28 (m, 3 H), 7.23-7.17 (m, 5 H), 20 7.01-6.98 (m, 2 H), 5.00 (br. ABq, JAB = 12 Hz, 2 H), 4.00 (br. s, 1 H), 3.55-3.50 (m, 1 H), 3.18 (d, J = 13 Hz) 3.14 (v. br. s, 1 H), 2.92 (d, J = 13.5 Hz), 2.74 (d, J = 13.4 Hz), 2.03-1.99 (m, 1 H), 1.63-1.50 (m, 3H), 1.39 (s, 9 H). 25 Step D:
HHCI
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (3.08 g, 7.52 mmol) in ethyl acetate (40 mL) and HC1 gas at 0°C for 15 minūtes (2.65 g, 100%). -292- FAB-MS calc. for C20H23NO2: 309; Found 310 (M+H)
Step E:
Prepared by the procedure described in Example Cl, Step D 15 from the intermediate prepared in the previous step (768 mg, 2.22 mmol), Intermediate 1 (720 mg, 1.85 mmol), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (2 eq.). Purification by MPLC, eluting with 50% ethyl acetate in hexane, provided two diastereomers. The isomer which came out first was designated as dl (504 mg, 40%) and the one 20 which eluted second was designated as d2 (474 mg, 38%) dl FAB-MS calc. for C40H48N4O6: 680; Found 681 (M+H) d2 FAB-MS calc. for C40H48N4O6: 680; Found 681 (M+H)
Step F:
-293- LV 11525
Prepared by the procedure described in Example Cl, Step C from the intermediate dl from Step E (25 mg, 0.036 mmol) in ethyl acetate (3 mL) and HC1 gas at 0°C for 10 minūtes (20.2 mg, 91%). FAB-MS calc. for C35H40N4O4: 580; Found 581 (M+H) EXAMPLE Cl 1
Prepared by the procedure described in Example Cl, Step C from the intermediate d2 (20.1 mg, 0.03 mmol) of Example CIO, Step E in ethyl acetate (3 mL) and HC1 gas at 0°C for 10 minūtes (12.8 mg, 70%). FAB-MS calc. for C35H40N4O4: 580; Found 581 (M+H) EXAMPLE C12
Step A: -294-
A suspension of 10% palladium on carbon (60 mg) and the intermediate (dl) from Example CIO, Step E (442.6 mg, 0.65 mmol) in ethanol (20 mL) was vigorously stirred under a hydrogen atmosphere for 30 minūtes. The reaction mixture was then filtered through celite and evaporated to give the product (376.0 mg, 98%). 15 dl FAB-MS calc. for C33H42N4O6: 590; Found 591 (M+H)
Step B:
20 25
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (211 mg, 0.357 mmol) and 30 HC1 gas in ethyl acetate (15 mL) at 0°C for 10 minūtes (175.6 mg, 93%). lH NMR (CD3OD, 400MHz): The compound exists in two rotamers in approximately a 1:1 ratio. δ 7.57-7.54 (m, 1 H), 7.38 (d, J = 8.2 Hz, 1/2 H), 7.33 (d, J = 8.2 Hz, 1/2 H), 7.25-7.00 (m, 8 H), 6.81-6.79 (m, 1 H), 5.36 (dd, J = 6 Hz, 8.5 Hz, 1/2 H), 5.18 (app t, J = 7.5 Hz, 1/2 H), 4.32 (br. d, J = 13 Hz, 1/2 H), 4.00 (br. d, J = 13 Hz, 1/2 H), 3.78 (br. d, J = 13 -295- LV 11525
Hz, 1/2 H), 3.26-3.02 (m, 11/2 H), 2.86 (d, J = 13.4 Hz, 1/2 H), 2.80 (d, J = 13.4 Hz, 1/2 H), 2.53 (d, J = 13.4 Hz, 1/2 H), 2.46 (d, J = 13.4 Hz, 1/2 H), 2.29 (dt, 1/2 H), 2.09 (d, J = 12.7 Hz, 1/2 H), 1.92-1.88 (m, 1/2 H), 1.55,1.50,1.44 (3s, 6 H), 1.40-1.25 (m, 1 H), 1.20-1.12 (m,l/2 H). 5 dl FAB-MS calc. for C28H34N4O4: 490; Found 491 (M+H) EXAMPLE C13
10 15
Step A: 20 25
Prepared similarly from the intermediate d2 (224.2 mg, 0.33 mmol) from Example CIO, Step E (169.3 mg, 87%). d2 FAB-MS calc. for C33H42N4O6: 590; Found 591 (M+H) 30 5 -296- Step B:
10
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (139 mg, 0.235 mmol)) and HC1 gas in ethyl acetate (15 mL) at 0°C for 10 minūtes (122.7 mg, 99%). 15 lH NMR (CD3OD, 400MHz): The compound exists as two rotamers in approximately a 1:1 ratio. δ 8.21 (d, J = 7.4 Hz, 1/2 H), 7.91 (d, J = 7.4 Hz, 1/2 H), 7.62 (d, J = 7.9 Hz, 1/2 H), 7.50 (d, J = 7.9 Hz, 1/2 H), 7.34-6.90 (m, 9 H), 5.40-5.34 (m, 1 H), 4.40 (d, J = 13.7 Hz, 1/2 H), 4.13 (d, J = 12.6 Hz, 1/2 H), 3.63 (d, J = 13.3 Hz, 1/2 H), 3.50 (d, J = 13.3 Hz, 1/2
20 H), 3.30-3.10 (m, 7/2 H), 2.93 (ABq, 1H), 2.88 (v. br. d, 1/2 H), 2.60 (d, J = 13 Hz, 1/2 H), 2.40 (d, J = 13 Hz, 1/2 H), 2.19-2.16 (m, 1/2 H), 1.78-1.75 (m, 1 H), 1.60-1.40 (m, 3/2 H), 1.20-1.10 (m, 1/2 H), 1.58, 1.50, 1.47,1.15 (4s, 6 H), 1.00-0.90 (m, 1/2 H). d2 FAB-MS calc. for C28H34N4O4: 490; Found 491 (M+H) 25
The additional examples shown in Table CV were prepared according to Examples CIO through C12 using Intermediate 3 and the intermediate obtained in Example CIO Step D. 30 -297 - LV 11525
TABLE CV: ADDITIONAL EXAMPLES
entry X MF FAB-MS (M+l) isomer 1 C02Bn C35H43N304 570 RS 2 C02H C28H37N304 480 RS EXAMPLE C14
Step A:
Boc
OEt
Ks? A solution of n-BuLi in hexane (4.9 mL, 12.36 mmol) was added to a stirred solution of 2,2,6,6-tetramethylpiperidine (TMP, 2.3 mL, 1.92 g, 13.5 mmol) in THF (25 mL) with ice-bath cooling. In a -298- separate flask, a stirred mixture of ethyl N-t-Boc-3-benzyl-nipecotate (Example Cl, Step B, 1.73 g, 5 mmol) and CH2B12 (0.78 mL, 2.15 g, 12.4 mmol) in THF (20 mL) was cooled to -78°C, and the Lithium salt solution of TMP solution just prepared was then added over a 15 minūte period at a temperature below -65°C. After 10 minūte, a solution of LHMDS (11.2 mL, 11.2 mmol) was added over a 10 minūtes period at -78°C. Following the addition, the cooling bath was removed and the mixture was allowed to warm gradually to 0°C. The mixture was cooled with an ice bath, and a solution of n-BuLi in hexane (13.5 mL, 33.7 mmol) was added at a temperature below 5°C over a 15 minūtes period. The mixture was warmed to room temperature and stirred for 45 minūtes. The mixture was cooled to -78°C and quenched over a 50 minūte period by adding it into a stirred solution of acidic ethanol (30 mL) at 0°C. The mixture was evaporated to dryness and suspended in dichloromethane (100 mL), to which was added triethylamine (0.7 mL, 5.0 mmol) and di-tert-butyl dicarbonate (1.09 g, 5.0 mmol) vvhile stirring. After 1 hour of stirring at room temperature, the material was washed with brine, dried, and concentrated. Purification by silica gel flash column chromatography, eluting with 10-30% ethyl acetate in hexane, provided the compound (1.44 g, 80%).
Step B: HHC1
OEt
Prepared by the procedure described in Example Cl, Step C, from the intermediate from the previous step (1.30 g, 3.56 mmol) and HC1 gas in ethyl acetate (50 mL) at 0°C for 45 minūtes (975 mg, 91%). FAB-MS calc. for C16H23NO2'. 261; Found 262 (M+H) -299- LV 11525
Step C:
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (55 mg, 0.21 mmol), Intermediate 1 (1 eq.), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (80 mg, 0.42 mmol). Purification by MPLC eluting with 60% ethyl acetate in hexane provided the compound (77 mg, 61.5%).
Step E:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (77 mg, 0.13 mmol) and HC1 gas in ethyl acetate (8 mL) at 0°C for 15 minūtes (59 mg, 85%). FAB-MS calc. for C31H40N4O4: 532; Found 533 (M+H) -300- EXAMPLE C15
Step A:
The intermediate from Example CIO, Step C (1.85g, 4.52 mmol) was hydrogenated over 1 atm of H2 and 10% palladium on carbon (150 mg) in ethanol (20 mL). Filtering through celite and evaporation yielded the acid (1.36 g, 94%). lH NMR (CDCI3,400 MHz) 5 7.27-7.19 (m, 3 H), 7.14-7.10 (m, 2 H), 4.08-3.59 (br. m, 1 H), 3.63-3.59 (m, 1 H), 3.15-3.05 (br. m, 2 H), 2.9. (d, J = 13.5 Hz, 1 H), 2.79 (d, J = 13.5 Hz, 1 H), 2.05-1.95 (br. m, 1 H), 1.70-1.45 (m, 3 H), 1.42 (s, 9 H). EI-MS calc. for C18H25NO4: 319; Found319 (M+,)
Step B:
Boc
NHEt -301- LV 11525
To a solution of the intermediate from the previous step (320.4 mg, 1.0 mmol) in dichloromethane containing ethyl amine hydrochloride (163 mg, 2.0 mmol), DMAP (1.0 eq.), and N-methyl moīpholine (2 eq.), was added EDC (2 eq.). The reaction mixture was 5 stirred at room temperature ovemight. The solution was vvashed with 3 N HC1 and brine, dried over anhydrous magnesium sulfate, then filtered and concentrated. Purification by silica gel flash column eluting with a gradient of 60-100% ethyl acetate in hexane provided the tītie compound (262 mg, 76%). lH NMR (CDCI3,400 MHz) δ 7.21-7.13 (m, 3 H), 7.03 10 (d, 2 H), 6.68 (br. s, 1 H), 4.18 (br. d, 1 H), 3.96 (br. d, 1 H), 3.12-3.00 (m, 4 H), 2.70-2.40 (br. m, 5 H), 1.60-1.50 (m, 1 H), 1.37 (s, 9 H), 1.20-1.30 (m, 1H), 0.90 (q, J = 7.3 Hz, 3 H). EI-MS calc. for C20H30N2O3: 346; Found 346 (M+) 15 Step C:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (262 mg, 0.76 mmol) and 25 HC1 gas in ethyl acetate (5 mL) at 0°C for 1 hour (194 mg, 90%). lH NMR (CD3OD, 400MHz) δ 8.28 (br. s, 1 H), 7.30-7.24 (m, 3 H), 7.14-7.12 (m, 2 H), 3.43 (d, J = 12 Hz, 1 H), 3.34-3.28 (m, 2 H), 3.26-3.20 (br. d, 1 H), 3.11 (d, J = 14 Hz, 1 H), 2.88 (dt, J = 3.2 Hz, 13 Hz, 1H), 2.81 (d, J = 12.5 Hz, 1 H), 2.77 (d, J = 14 Hz, 1 H), 2.24 (d, J = 13 Hz, 1 H), 1.87 (td, J = 2.8 Hz, 14 Hz, 1 H), 1.75 (dt, J = 3.3 Hz, 13.5 Hz, 1 H), 1.64-1.55 (m, 1 H), 1.17 (t, J = 7 Hz, 3 H). 30 5 -302- Step D:
10
Prepared by the procedure described in Example Cl, Step D from intermediate prepared in the previous step (62.2 mg, 0.22 mmol), Intermediate 1 (1 eq.), HOBT (1 eq.), N-methyl morpholine (1 eq.), and 15 EDC (2 eq.). Purification by MPLC eluting with ethyl acetate provided two diastereomers, the one which was eluted out of the column first was designated as dl (35.8 mg, 26%) and the one came out second was designated as d2 (43.8 mg, 31%). d2. lH NMR (CD30D, 400 MHz): The compound exists in two 20 rotamers in approximately a 1:1 ratio. 6 8.16 (br. s, 1/2 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.25-6.96 (m, 8 H), 6.69 (br. s, 1/2 H), 5.28-5.12 (m, 1/2 H), 4.94 (v. br. m, 1/2 H), 4.31 (br. d, J = 14.6 Hz, 1/2 H), 3.49 (v. br. d, J = 13 Hz, 1/2 H), 3.22 (dd, J = 4.7 Hz, 14.3 Hz, 1/2 H), 3.03-2.97 (m, 2 H), 2.90 (d, J = 13.4 Hz, 1/2 H), 2.40 (br. d, 1/2 H), 25 2.36 (d, J = 13.3 Hz, 1/2 H), 2.10 (d, J = 13.5 Hz, 1/2 H), 1.92-1.82 (br. m, 3/2 H), 1.47 (s, 3 H), 1.41 (s, 9 H), 1.38 (s, 3 H), 1.32-1.20 (m), 1.10-1.00 (dt, 1/2 H), 0.85 (t, J = 7.2 Hz, 3 H). dl FAB-MS calc. for C35H47N5O5: 617; Found 618 (M+H) d2 FAB-MS calc. for C35H47N5O5: 617; Found 618 (M+H) 30 -303- LV 11525
Step E:
Prepared by the procedure described in Example Cl, Step C from the Intermediate dl from the previous step (35 mg, 0.057 mmol) and HC1 gas in ethyl acetate (3 mL) at 0°C for 30 minūtes (32.5 mg, 100%). FAB-MS calc. for C30H39N5O3: 517; Found 518 (M+H) EXAMPLE C16
Prepared by the procedure described in Example Cl, Step C from the intermediate d2 from Example C15, Step D (41 mg, 0.066 mmol) and HC1 gas in ethyl acetate (3 mL) at 0°C for 30 minūtes (36.5 mg, 100%). lH NMR (CD3OD, 400 MHz): The compound exists in two rotamers in approximately a 4:1 ratio. δ 8.21 (d, J = 7.4 Hz, 4/5 H), 8.02 (d, J = 7.4 Hz, 1/5 H), 7.68 (d, J = 7.8 Hz, 1/5 H), 7.54 (d, J = 7.8 Hz, 4/5 H), 7.35 (d, J = 7.1 Hz, 4/5 H), 7.31 (d, J = 7.1 Hz, 1/5 H), 7.26-6.98 (m, -304- 8 Η), 5.46-5.40 (m, 1/5 Η), 5.25-5.20 (m, 4/5 Η), 4.00 (br. d, 4/5 Η), 3.85 (br. d, 1/5 H), 3.65 (br. d, J = 13.2 Hz, 4/5 H), 3.60-3.54 (m, 1/5 H), 3.36 (br. d, 1/5 H), 3.30-3.03 (m), 2.99-2.90 (m), 2.82-2.62 (m), 2.46 (d, J = 13.3 Hz, 8/5 H), 2.08 (br. d, 4/5 H), 1.90-1.84 (m, 1/5 H), 1.76-1.65 (m), 5 1.51,1.49 (2s, 6 H), 1.40-1.20 (m), 1.00 (t, J = 7.2 Hz, 3/5 H), 0.88 (t, J ’= 7.2 Hz, 12/5 H). FAB-MS calc. for C30H39N5O3: 517; Found 518 (M+H)
To a suspension of the S- isomer intermediate of Step A of Exaraple C2 (27.3 g, 68.8 mmol) in 3 N sodium hydroxide (25 mL), dichloromethane (200 mL) and water (100 mL), was slowly added di-t- 30 butyl dicarbonate (18 g, 1.2 equiv.). The mixture was stirred for an additional 5 hours after the addition, it was acidified to pH 3 carefully and then extracted with ethyl acetate three times. The organic extracts were combined, dried, and concentrated to give a vvhite solid (23.7 g). -305- LV 11525 A solution of this intermediate (11.5 g, 33.1 mmol) and 3 N NaOH (30 mL) in ethanol (200 mL) and water (10 mL) was refluxed for one day. The solution was evaporated to remove ethanol, and then acidified with 3 N HC1 to pH=3 and extracted with ethyl acetate. The extract was dried, evaporated and purified by a short silica gel column, initially eluting with 20% ethyl acetate in hexane, then with ethyl acetate to give the product (8.76 g, 83%). NMR and MS were identical to Example C15 stepA.
Step B 10
Boc
15
To a mixture of the intermediate from the previous step (660 mg, 2.07 mmol), ethylamine hydrochloride (251 mg, 1.5 equiv.), NMM (0.23 mL, 1 equiv.) and HOBT (1 eq) in dichloromethane and DMF (1:1, 20 10 mL) was added EDC. The mixture was stirred at room temperature for two days, heated at reflux for 2 hours, and was poured into a dilute HC1 and brine mixture. It was extracted with ethyl acetate, and the organic layer was washed with dilute NaOH, dried and evaporated. Purification by flash column eluting with 20-80% ethyl acetate in hexane 25 gavē the product (540 mg, 75%). NMR and MS were identical to Example C15 Step B.
Step C
HHCI NL
NHEt O Ύ 30 -306-
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (0.33 g, 0.95 mmol) in ethyl acetate (5 mL) and HC1 gas at 0°C for 15 minūtes (0.279 mg, 100%). FAB-MS calc. for C15H22N2O: 246 ; Found 247 (M+H)
Step D
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (100 mg, 0.354 mmol), Intermediate 3 (134 mg , 0.354 mmol), HOBT (48 mg, 1 eq.), N-methyl morpholine (0.039 mL, 1 eq.), and EDC (102 mg, 1.5 eq.). Purification by MPLC, eluting with ethyl acetate, provided the 20 intermediate (140 mg, 65%). FAB-MS calc. for C35H50N4O5: 606 ; Found 607 (M+H)
Step E
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (132 mg, 0.217 mmol) and HC1 gas in ethyl acetate (5 mL) at 0°C for 10 minūtes (113.3 mg, 96%). -307- LV 11525 dl FAB-MS calc. for C30H42N4O3: 506, Found: 507 (M+H)
The additional intermediates shown in Table CVIa were prepared according to the above established procedure as exemplified in Example C15, and Example C17 steps A through C,. The final compounds were prepared according to Example C17 Steps D and E, using Intermediate 1.
TABLE CVIa: ADDITIONAL EXAMPLES 10 15
H
X Bn Intermediate
Intermediate Product entry X MF MF isomer FAB-MS (M+l) FAB-MS (M+l) 1 -CO(morpholino) C17H24N2O2 C32H41N5O4 S 288 (M+, EI) 560 2 -CONHCH3 C14H20N2O C29H37N5O3 S 233 504 3 -CONH- C17H24N2O3 C32H41N5O5 s CH2C02Et 304 (M+, EI) 576 4 -C02CH2C02Et C17H23NO4 C32H40N4O6 R 306 577 S 5 -C02(CH2)2SMe CI6H23NO2S C31H4ON4O4S R 294 565 S 6 -CON(CH3)2 C15H22N20 C30H39N5O3 dl 247 518 d2 7 -CONH- C15H22N2O2 C30H39N5O4 S (CH2)20H 263 534 -308-
Likevvise using 3-aminopropanol or 2-(ethylthio)ethylamine it is possible to prepare the compounds shown in Table CVIb using Intermediate 1. -308- TABLE CVIb
2 -CONHCH2CH2SCH3
The additional compounds shovvn in Table CVIc \vere prepared according to Examplel7 Steps C and D, using some of the intermediates shovvn in Table CVIa and Intermediate 3.
TABLE CVIc: ADDITIONAL EXAMPLES
entry Y MF FAB-MS (M+l) īsomer -309- LV 11525
1 -CO(morpholino) C32H44N4O4 S 549
2 -CONHCH3 3 -CONH- CH2C02Et 4 -CONH- (CH2)20H C29H40N4O3 S 493 C32H44N4O5 S 565 C30H42N4O4 S 523
Likewise using 3-aminopropanol and 2-(methylthio)-ethylamine it is possible to preparē the compounds shovvn in Table CVId. TABLE CVTd
entry X_
1 -CONH(CH2)30H 2 -CONHCH2CH2SCH3
The additional compounds shovvn in Table CVIe vvere prepared according to Examplel7 Steps C and D, using some of the intermediates shovvn in Table CVI and Intermediate 2. 5 - 310 -
TABLE CVIe: ADDITIONAL EXAMPLES 10
Ph^O/^N'y><>JH2 HCI C=0 O
15 entry Y MF FAB-MS (M+l) isomer 1 -CO(morpholino) C31H42N4O5 551 S 2 -CONHCH3 C28H38N4O4 495 S 3 -CONH- CH2C02Et C31H42N4O6 567 S EXAMPLE C18 20
Π-ίί^Γ Y^NH2 hci 25
N i C=0 O
<OH 30 -311 - LV 11525
Step A:
Boc
To a stirred solution of ethyl N-t-Boc-3-phenylmethyl 10 nipecotate (10.4 g, 29.93 mmol) in dichloromethane (100 īnL) at -78°C was added DIBAL (1M, 45 mL). The reaction was stirred at -78°C for 4 hours and quenched by the addition of methanol (5 mL). The reaction mixture was washed carefully with tartaric acid water solution and brine, dried over MgS04 and evaporated. Silica gel flash chromatography 15 eluting with a gradient of 40-80% ethyl acetate in hexane yielded the product (6.81 g, 75%). EI-MS calc. for CI8H27NO3: 305; Found 305 (M+)
Step B: 20 3-Phenylmethvl-3-piperidinemethanol hvdrochloride
HHCI
OH 25 A solution of the intermediate from the previous step (770 mg, 2.52 mmol) in ethanol (20 mL) and concentrated HC1 (1 mL) was refluxed for 3 hours. The reaction mixture was cooled to room 3 0 temperature and evaporated to give the title compound as a white solid. (609.0 mg, 100%) 1H NMR (CD3OD, 400 MHz) δ 7.31-7.19 (m, 5 H), 3.45 (ABq, J = 11 Hz, 2 H), 3.18 (d, J = 13 Hz, 1 H), 3.19-3.13 (m, 1 H), 3.03-2.99 (m, 1 H), 2.96 (d, J = 13 Hz, 1 H), 2.72 (s, 1 H), 1.92-1.84 (m, 2 H), 1.60-1.50 (m, 2 H). -312- EI-MS calc. for C12H17NO: 191; Found 191 (M+) Step C: -312-
Prepared by the procedure described in Example Cl, Step D 15 from the intermediate prepared in the previous step (142 mg, 0.587 mmol), Intermediate 1 (0.8 eq.), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (2 eq.). Purification by MPLC eluting with ethyl acetate gavē two compounds; the compound which came out of the column first is designated as dl (98.5 mg, 58%) and the compound which came out of 20 the column next as d2 (34.5 mg, 12%) dl FAB-MS calc. for C32H42N4O5: 562; Found 563 (M+H) d2 FAB-MS calc. for C32H42N4O5: 562; Found 563 (M+H)
Step D: 25
- 313 - LV 11525
The intermediate (dl) from the previous step (60 mg, 0.104 mmol) was treated with HC1 gas at 0°C in ethyl acetate (3 mL) for fīve minūtes. Evaporation gavē the diastereomer 1 of the title compound. dl FAB-MS calc. for C28H36N4O3:476; Found 477 (M+H)
The intermediate (d2) from Step C (20 mg) was treated with HC1 gas at 0°C in ethyl acetate (3 mL) for fīve minūtes. Evaporation gavē the diastereomer 2 of the title compound. d2 FAB-MS calc. for C28H36N4O3: 476; Found 477 (M+H) EXAMPLE C19
Step A:
Boc
.N,
To a stirred solution of intermediate from Example C18, Step A (5.12 g, 16.8 mmol), and triethylamine (4.7 mL) in dichloromethane at 0°C was added mesyl chloride (1.95 mL). The reaction mixture was stirred for 2 hours. The solution was poured into a mixture of brine and 3 N HC1 and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over -314- magnesium sulfate and evaporated to yield the mesylate. The mesylate was heated with sodium azide (2.2 g, 33.6 mmol) in DMSO (20 mL) at 80°C for two weeks. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 5 saturated sodium bicarbonate and brine; it was dried, and evaporated. Purification by silica gel flash column chromatography provided the azide (4.14 g, 75%). 1H NMR (CDCI3, 200 MHz) δ 7.29-7.13 (m, 5 H), 3.61-3.57 (br. m, 1 H), 3.47 (d, J = 12 Hz, 1 H), 3.20-3.10 (v. br. s, 2 H), 3.10-2.96 (v. br. d, 10 1 H), 2.60-2.45 (br. m, 2 H), 1.65-1.48 (m, 4 H), 1.44 (s, 9 H), 1.41-1.35 (m, 1 H). FAB-MS calc. for C18H26N4O2: 330; Found 331 (M+H)
The azide from the previous step (1.60 g, 4.84 mmol) was hydrogenated over 10% palladium on carbon (160 mg) in ethanol (25 mL) under a 1 atm hydrogen balloon for 2 hours. The reaction mixture was filtered through celite and evaporated to give the amine (1.42 g, 96%). FAB-MS calc. for C18H28N2O2: 304; Found 305 (M+H)
Step D:
Boc NHCbz 30 -315- LV 11525
To a stirred solution of the amine ffom the previous step (1.30 g, 4.27 mmol) in dichloromethane (20 mL) which also contained DMAP (20 mg) and triethylamine (1 mL) at 0°C, was added CbzCl (0.73 mL, 5.12 mmol). The reaction mixture was stirred for 2 hours. The 5 solution was poured into a mixture of brine and 3 N HC1 and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to give a residue which was purified by flash chromatography, eluting with 20% ethyl acetate in hexane, to yield the product (1.52 g). 10 FAB-MS calc. for C26H34N2O4: 438; Found 439 (M+H)
Step E:
HHCI
NHCbz 15
To a stirred solution of the intermediate from the previous step (1.50 g, 3.42 mmol) in ethyl acetate (50 mL) at 0°C was bubbled HC1 until it was saturated. The reaction mixture was stirred for one hour and evaporated to yield the salt (1.32 g, 100%). lH NMR (CD3OD, 400MHz) δ 7.40-7.18 (m, 10 H), 5.14 (s, 2 H), 3.43, 25 3.42 (2 d, J = 14. 8 Hz, 1 H), 3.23 (td, J = 4 Hz, 12.1 Hz, 1 H), 3.00 (d, J = 13 Hz, 1 H), 2.94 (d, J = 14.7 Hz, 1 H), 2.83 (dt, J = 3.4 Hz, 12 Hz, 1 H), 2. 74 (d, J = 13 Hz, 1 H), 2.68 (d, J = 13.6 Hz, 1 H), 2.62 (d, J = 13.6 Hz, 1 H), 2.00-1.90 (m, 1 H), 1.92-1.88 (m, 1 H), 1.59-1.52 (m, 1 H), 1.47-1.44 (m, 1H). 30 FAB-MS calc. for C21H26N2O2: 338; Found 339 (M+H) 5 -316- Step F:
10
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (1.00 g, 2.67 mmol), Intermediate 1 (1.04 g, 1 eq.), HOBT (1 eq.), N-methyl morpholine (2 15 eq.), and EDC (820 mg, 4.27 mmol). Purification by MPLC, eluting with 60% ethyl acetate in hexane, provided the compound. (1.54 g, 81%)
Step G:
The intermediate from the previous step (1.30 g, 1.83 mmol) was hydrogenated over 10% palladium on carbon (100 mg) in ethanol (15 mL) under a hydrogen balloon. The reaction mixture was filtered through celite and evaporated to yield the amine (1.20 g, 100%). FAB-MS calc. for C33H45N5O4: 575; Found 576 (M+H) -317- LV 11525
Step H:
To a stirred solution of the intermediate prepared the previous step (286 mg, 0.497 mmol), DMAP (10 mg) and N-methyl morpholine (0.109 mL) in dichloromethane (10 mL) at 0°C was added 15 mesyl chloride (0.042 mL). The reaction mixture was stirred for 2 hours. The solution was poured into a mixture of brine and 3 N HC1 and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate dried over magnesium sulfate and evaporated to give a residue which was purified by flash 20 chromatography, eluting with 90% ethyl acetate in hexane, to give the product (285.9 mg, 88%). FAB-MS calc. for C34H47N5O6S: 653; Found 654 (M+H)
Step I: 25
30 -318-
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (265 mg, 0.405 mmol) and HC1 gas in ethyl acetate (8 mL) at 0°C for 30 minūtes (189 mg, 79%) FAB-MS calc. for C29H39N5O4S: 553; Found 554 (M+H) EXAMPLE C20
Prepared by the procedure described in Example Cl, Step C from the intermediate from Example 09, Step F (109 mg, 0.154 mmol) 20 and HC1 gas in ethyl acetate (4 mL) at 0°C for 30 minūtes (90 mg, 90%). FAB-MS calc. for C36H43N5O4: 609; Found 610 (M+H) EXAMPLE C21
- 319 - LV 11525
Step A;
The mixture of the intermediates from Example 09, Step G (208 mg, 0.362 mmol) and pyridine (2 mL) and acetic anhydride (2 mL) was heated at 60°C for 30 minūtes. The mixture was then evaporated under vacuum. MPLC purifīcation eluting with 80% ethyl acetate in hexane yielded the product (202 mg, 90%). FAB-MS calc. for C35H47N5O5: 617; Found 618 (M+H)
Step B:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (192 mg, 0.311 mmol) and HC1 gas in ethyl acetate (4 mL) at 0°C for 30 minūtes (168.1 mg, 98.5%). FAB-MS calc. for C30H39N5O3: 517; Found 518 (M+H) -320- EXAMPLE C22
A suspension of platinum (IV) oxide (200 mg), ethyl 3-pyridylacetate (5.0 g, 30.3 mmol) and concetrated hydrochloric acid (10 mL) in ethanol (50 mL) was stirred under a hydrogen balloon ovemight. The mixture was filtered through celite and evaporated to yield a residue, which was refluxed with anhydrous acidic ethanol for 30 minūtes. Evaporation yielded the product (6.28 g, 100%). lH NMR (CD3OD, 400MHz) δ 4.13 (q, J = 7.2 Hz, 2 H), 3.40 (dd, J = 3.5 Hz, 12 Hz, 1 H), 3.35 (br. d, 1 H), 2.90 (br. t, 1 H), 2.73 (t, J = 12 Hz, 1 H), 2.35 (d, J = 7.5 Hz, 2 H), 2.26-2.17 (m 1 H), 1.96-1.80 (br. m, 2 H), 1.80-1.70 (m, 1 H), 1.37-1.26 (m, 1 H), 1.24 (t, J = 7.1 Hz, 3H).
Step B:
-321 - LV 11525
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (128 mg, 0.617 mmol), Intermediate 1 (200 mg, 0.514 mmol), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (200 mg). Purifīcation by MPLC eluting with 80% ethyl acetate in hexane provided the compound. (247 mg, 89%)
Step C:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (225 mg, 0.415 mmol) and HC1 gas in ethyl acetate (5 mL) at 0°C for 15 minūtes (184 mg, 100%). FAB-MS calc. for C24H34N4O4: 442; Found 443 (M+H) EXAMPLE C23
5 -322- Step A:
Boc
fsL
O
OH
The less polar (dl) intermediate from Example C8 step A ( 10 7.25g, 17.08 mmol) was refluxed for 8 hours in ethanol (20 ml) and 10N
NaOH (8.5 mL). The mixture was then cooled to room temperature and slowly treated with 3 N HC1 to pH=l 1. To this stirred solution was added di-tert-butyl dicarbonate in dioxane (20 mL) and stirred for two hours. The solution was acidified to pH 4 and then neutralized to pH 7 15 and extracted with ethyl acetate three times. The organic extracts were combined, dried, and concentrated to give white solid (6.80g). FAB-MS calc. forCi7H24N204: 320, Found: 321 (M+H)
Step B: 20
Boc
NL
OBn 25
To a solution of the intermediate from the last step (6.5 g), benzyl alcohol (2 equiv.), and DMAP (20 mg) in dichloromethane (100 mL), was added EDC (1.2 equiv.). The mixture was stirred at room temperature for three days, and was poured into dilute NaHC03 solution It was extracted with ethyl acetate three times, and dried over MgS04. Evaporation and purification by a flash column eluting with 40% ethyl acetate in hexane gavē the desired product.(6.53 g, 78%). FAB-MS calc. for C24H30N2O4: 410 ; Found 411 (M+H); 311 (M+-Boc(100)). 30 LV 11525 5
Step C:
-323-H HCI
Prepared by the procedure described in Example Cl, Step C 10 from the intermediate from the previous step (1.0 g, 2.44 mmol) in ethyl acetate (40 mL) and HCI gas at 0°C for 15 minūtes (935 mg, 99%). FAB-MS calc. for C19H22N2O2: 310 ; Found 311 (M+H)
Step D: 15
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (800 mg,2.09 mmol), intermediate 1 (812 mg , 2.09 mmol), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (2 eq.). Purification by MPLC, eluting with 80% ethyl acetate in hexane, provided the Intermediate (1.10g, 77%) dl FAB-MS calc. for C39H47N5O6: 681; Found 682 (M+H) 30 -324-
Step E:
A suspension of 10% palladium on carbon (150 mg) and the intermediate from previous step (1.05 g, 1.54 mmol) in ethanol (20 mL) was vigorously stirred under a hydrogen atmosphere for 30 minūtes. The reaction mixture was then filtered through celite and evaporated to give the product (828 mg, 91%). dl FAB-MS calc. for C32H41N5O6 : 591 ; Found 592 (M+H)
Step F:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (211 mg, 0.357 mmol) and HC1 gas in ethyl acetate (15 mL) at 0°C for 10 minūtes (175.6 mg, 93%). dl FAB-MS calc. for C27H33N5O4: 491 Found 492 (M+H) -325 - LV 11525 F.XAMPLE C24
To a stirred solution of the product from Example C23, step A (5.79 g, 18.1 mmol), 2-(methylthio)ethanol (2.49 g, 27.1 mmol), DMAP (220 mg) in dichloromethane (100 mL) was added EDC and the mixture was stirred for one day. The reaction mixture was washed with brine, dried, evaporated, and purified on silica gel column eluting with 60% ethyl acetate in hexane to give the desired compound (6.64 g, 94%) FAB-MS calc. for C20H30N2O4S: 394, Found: 395 (M+H)
H HCI
0(CH2)2SCH3
Step B:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step(6.12 g, 15.5 mmol) in ethyl acetate (30 mL) and HCI gas at 0°C for 30 minūtes (5.38 g, 95%). FAB-MS calc. for C15H22N2O2S: 294 ; Found 295 (M+H)
Step C:
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (2.0 g, 5.44 mmol), Intermediate 1 (2.12, 5.44 mmol), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (1.5 eq.). Purification by MPLC, eluting with 80-100% ethyl acetate in hexane, provided the intermediate (3.44g, 95%) FAB-MS calc. for C35H47N5O6S: 665 ; Found 666(M+H)
Step D:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step(2.94 g, 4.42 mmol) in ethyl acetate (10 mL) and HC1 gas at 0°C for 20 minūtes (2.80 g, 99%). FAB-MS calc. for C30H39N5O4S: 565 ; Found 566(M+H) . r
The additional intermediates shown in Table CVII were prepared according to the above established procedure as exemplified in Example C24, steps A and B,. The final compounds were prepared according to Example C17 Steps D and E, using Intermediate 1. -327- LV 11525
TABLE CVII 5 10
MF MF FAB-MS(M+1) FAB-MS(M-fl) 1 C02(CH2)2SMe C15H22N2O2S 295 C30H39N5O4S 566 2 C02Bn C19H22N2O2 311 C34H39N5O4 582 3 C02Bn C19H22N2O2 311 C34H39N5O4 582 20 4 C02(CH2)3CH3 C16H24N202 277 C31H41N5O4 548 5 C02(CH2)2CH3 C15H22N2O2 263 C30H39N5O4 534 6 C02CH(CH3)2 C15H22N2O2 263 C30H39N5O4 534 25 7 CONH(CH2)3CH3 C16H25N30 276 C31H42N6O3 547 8 CONHCH(CH3)2 C15H23N3O 262 C30H40N6O3 533 9 C02CH2C02Et C16H22N2O4 306 C31H39N5O6 578 10 CONHEt C14H21N3O C29H38N6O3 248 519 30 11 C0NHCH2C02Et C16H23N3O3 307 C31H40N6O5 577 Note: RS compounds were prepared by using racemic intermediates instead of chiral ones.
R R S RS RS RS RS RS RS RS RS -328-
EXAMPLE C24A
To a stirred solution of the final product from Example C24 (120 mg, 0.188 mmol) in ethanol/water (3/2 mL), was added sodium periodate (100 mg, 0.467 mmol) and the resulting mixture was stirred at room temperature for six hours. The reaction mixture was then poured into saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL, 3 times). The organic extracts were combined and evaporated to give the desired compound (89 mg, 81%). FAB-MS calc. for C30H39N5O5S: 581 ; Found 582(M+H) EXAMPLE C25
- 329- LV 11525
Step A:
To a stirred solution of the intermediate from Example C23, step E (100 mg, 0.17 mmol), 3-(methylthio) propanol (18 mg, 0.17 mmol) and DMAP (3 mg) in dichloromethane (15 mL) was added EDC (1.5 equiv.), and the mixture was stirred at room temperature for one day. The reaction mixture was washed with water and brine, dried, evaporated and purified by MPLC eluting with 80% ethyl acetate in hexane to give the desired compound (88 mg). FAB-MS calc. for C36H49N5O6S: 679 ; Found 680(M+H)
Step B:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step(85 mg, 0.125 mmol) in ethyl acetate (3 mL) and HC1 gas at 0°C for 20 minūtes (74 mg, 95%). FAB-MS calc. for C31H41N5O4S: 579 ; Found 580(M+H) -330-
The compounds shown in Table CVIII were prepared according to the above established procedure as exemplified in Example C25 using appropriate amines and alcohols.
TABLE CVTTT
entry X MF _FAB-MS(M+1) 1 CO(morpholine) C31H40N6O4 560 (M+EIMS) 2 C02(CH2)4SMe C32H43N5O4S 594 3 CONH(CH2)2SMe C30H40N6O3S 565 4 CONHEt C29H38N6O3 519 5 CONH(CH2)20H C29H38N6O4 535
Likewise using the intermediate from Example C23, Step C and follovving the procedures described in Step D and E using Intermediate 3 instead of Intermediate 1, the compounds shown in Table CVIIIa were prepared according to the established procedures as exemplified in Example C25 using appropriate amines. -331 - LV 11525 TABLE CVIIIa
_FAB-MS(M+1) 1 CONHEt C29H41N5O3 508 2 CONH(CH2)20H C29H41N5O4 524
Likewise using the intermediate from Example C23, Step E and foliowing the procedure described above; or the intermediate from Example C23, step A and foliowing the procedure described in Example C24 steps A through D using Intermediate 1 or Intermediate 3 the compounds shown in Table CVIIIb may be prepared. TABLE CVIIIb
X entry R1 1 -332- 1 -332-
2 3 4 5
^(CH2)3- -CONHCH3 -CONHCH3
-CONH(CH2)30H
-CONH(CH2)30H -CONHCH2CH2SCH3 EXAMPLEC26
Step A: 3-Carbobenzvloxvaminopyridine
To a solution of 3-aminopyridine (10 g, 0.106 mol) and triethyl amine (16.3 mL, 0.117 mol) in dichloromethane (100 mL) at 0°C, was added benzyl chloroforaiate (15.2 mL, 0.106 mol) slowly. The reaction mixture was stirred ovemight and was washed with water, saturated NaHC03, dried over MgS04, and evaporated. The residue was purified on a silica gel column to give the product (9.51 g) FAB-MS calc. for C13H12N2O2: 228 ; Found 229(M+H)
Step B: 3-CarbobenzvĪoxvaminopiperidine -333- LV 11525 A solution of the intermediate from the previous step (9.51 g, 41.7 mmol) and hydrochloric acid (3.5 mL, 41.7 mmol) in ethanol (300 mL) was hydrogenated over Pt02 (0.9 g) and hydrogen (1 atm) ovemight. Filtration and evaporation gavē the product as a brown solid. 5 FAB-MS calc. for C13HI8N2O2: 234 ; Found 235(M+H) 10
Step C:
^ NHCBZ
To a solution of the intermediate from the previous step 15 (4.65 g, 17.2 mmol), Intermediate 1 (6.68 g, equiv.), HOBT (2.32 g, 1 equiv.) and NMM (2.1 mL, 1 equiv.) in dichloromethane (100 mL), was added EDC (3.94 g, 1.2 equiv.). The reaction mixture was stirred ovemight and worked up by washing with water, saturated NaHC03, dried over MgS04 and evaporated. Purification on a S1O2 column gavē 20 2.5 g of the desired product. FAB-MS calc. for C33H43N5O6: 605 ; Found 606(M+H)
Step D:
A suspension of the intermediate from the previous step (2.5 g) and Pd(OH)2/C (250 mg, 10 %) in methanol (60 mL) was stirred under H2 (1 atm) for three days. The reaction mixture was filtered through celite and evaporated to give the desired material. FAB-MS calc. for C25H37N5O4: 471; Found 472(M+H) -334-
Step E:
To a solution of the intermediate from the previous step (236 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.6 mmol) in dichloromethane (10 mL), was added isobutyryl chloride (0.053 mL, 0.5 mmol) at 0°. The reaction mixture was stirred for 2 hours and was washed with water, brine, dried over MgS04 and evaporated. Si02 flash column chromatography eluting with 90-100% ethyl acetate in hexane yielded the product. FAB-MS calc. for C29H43N5O5: 541 ; Found 542(M+H)
Step F:
To a solution of the intermediate from the previous step in ethyl acetate (5 mL) at 0°C was bubbled HC1 until it was saturated. The mixture was stirred for 30 minūtes and evaporated to dryness to give the product. FAB-MS calc. for C24H35N5O3: 441 ; Found 442(M+H)
Similarly the following compounds were prepared according to the same procedure as described above, but using different acylating reaģents. -335- LV 11525
TABLE CIX
entry Acylating aģent Y MF FAB-MS(M+1) 1 Ac20 AcNH C22H31N5O3 414 2 ChxCOCl ChxCONH C27H39N5O3 482 3 ChxCH2COCl ChxCH2CONH C28H41N5O3 496 4 BzCl BzNH C27H33N5O3 476 5 PhS02Cl PhS02NH C26H33N5O4S 512 6 iso-PrNCO iso-PrNHCONH C24H36N603 457 note: Chx: cyclohexyl, Bz: benzoyl EXAMPLE C27
Step A:
-336- Boc f\L α C02Et
To a stirred solution of KHMDS (27.4 g, 0.138 mol) in THF (500 mL) at -78°C under argon was added ethyl N-t-Boc nipecotate (28.3 g, 0.11 mol) in THF (100 mL) over a 20 minūte period. The solution was allovved to stir an additional 30 minūtes at -78°C. Then, a solution of 4-bromomethylthiazole or 4-chloromethylthiazole in THF (100 mL) was added slowly to the reaction mixture. 4-Bromomethylthiazole was prepared by refluxing 4-methylthiazole (10 mL, 0.11 mmol), N-bromosuccinimide (19.6 g, 0.11 mol) and AIBN (0.2 g) in CCI4 (300 mL) for 2 hours, cooled to room temperature, filtered and evaporated; 4-chloromethylthiazole can be prepared as described by Hsiao, C-H et al, Synthetic Communications, 20 (22), 3507-3417 (1990) and Caldvvell, W and Fox, S.M. J. Am. Chem. Soc. 73,2935 (1955). The resulting black mixture was stirred ovemight and allowed to warm to room temperature. The material was concentrated, then diluted with water, and extracted using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography eluting with a solvent gradient of 30-65% ethyl acetate in hexane provided the title compound. (7.58 g, 20%). FAB-MS calc. for C17H26N2O4S 354; Found 355 (M+H)
Step B:
HHCI
- 337 - LV 11525
To a solution of the intermediate from the previous step (7.0 g, 19.8 mmol) in ethyl acetate (100 mL) at 0°C, was bubbled hydrogen chloride gas until saturation occurred. The reaction was stirred for 30 minūtes, and then concentrated to remove the ethyl acetate to afford the 5 product (5.3g, 93%). lH NMR (CDCI3, 400MHz) δ 9.67 (s, 1 H), 7.75 (s, 1 H), 4.34-4.15 (2 m, 2 H), 3.67 (d, J=12.8 Hz, 1 H), 3.34 (d, J=15 Hz, 1 H), 3.28 (d, J=12.5 Hz, 1 H), 3.21 (d, J=15 Hz, 1 H), 3.01 (dt, J=3.0, 12.5 Hz, 1 H), 2.26 (br. d, J=13.7 Hz, 1 H), 1.97-1.92 (m, 1 H), 1.80 (dt, J=3.5,13 Hz, 1 H), 1.78-1.58 (m, 1 H), 1.26 (t, J=7.2 Hz, 3 H). FAB-MS 10 calc. for C12H18N2O2S: 254 ; Found 255 (M+H)
Step C: 15 °Y^Ph °YSh 20 OAc OAc
25
To a stirred solution of the intermediate (6g, 18.67 mmol) prepared in Step B, (R)-(-)-(0)-acetyl mandelic acid (1 eq.), HOBT (1 eq.) and NMM (2 eq.) at 0°C was added EDC (7.16g, 37.34 mmol). The reaction mixture was stirred ovemight during which time it was allowed to warm to room temperature. The solution was poured into brine and extracted with CH2C12. The organic layer was dried over MgS04, evaporated and purified with a S1O2 flash column eluting with 40-80% ethyl acetate in hexane to provided two enantiomerically pure compounds. The isomer which came out of the column first was designated as dl (2.17 g, 30%) and the isomer which came out of the column second as d2 (0.87 g, 12%) and mixed fractions (700 mg). The initial stereochemistry assignment was made by NMR comparison of these compounds with the intermediates obtained in Example C8 Step A. The absolute stereochemistry of those intermediates was established by X-ray analysis. The assignment was later confīrmed by an X-ray analysis 30 -338- of Intermediate 1. FAB-MS calc. for C22H26N2O5S: 430 ; Found 431(M+H) dl: lH NMR (CDCI3,400MHz) indicated the compound exists as a mixture of two confoimers. 5 8.77, 8.65 (2 s, 1 H), 7.46-7.34 (m, 5 H), 7.07, 7.02 (2 s, 1 H), 6.64, 6.23 (2s, 1 H), 4.29 (br. d, J=13.9 Hz, 1/2 H), 4.10-4.02 (m, 3/2 H), 3.92-3.87 (m, 3/2 H), 3.61 (d, J=13.5 Hz, 1/2 H), 3.46 (d, J=14 Hz, 1/2 H), 3.40-3.32 (m, 1/2 H), 3.25-3.21 (m, 1/2 H), 3.18 (d, J=14 Hz, 1/2 H), 3.06 (d, J=14 Hz, 1/2 H), 2.96 (d, J=14 Hz, 1/2 H), 2.84 (d, J=14 Hz, 1/2 H), 2.85-2.75 (br. m, 1/2 H), 2.14,2.11 (2s, 3 H), 1.90-1.82 (m, 1 1/2 H), 1.80-1.75 (m, 1 H), 1.61-1.55 (m, 1 H), 1.50-1.40 (br. m, 1/2 H), 1.14 (t, J= 7 Hz, 3/2 H), 1.03 (t, J= 7 Hz, 3/2 H). d2: lH NMR (CDCI3, 400MHz) indicated the compound exists as a mixture of two conformers. δ 8.71, 8.68 (2d, J=1.8 Hz, 1 H), 7.41-7.34 (m, 5 H, 7.06, 6.83 (2 d, J=1.8 Hz, 1 H), 6.41 6.20 (2s, 1 H), 4.46 (br. d, J=13.4 Hz, 1/2 H), 4.24-3.93 (m, 3 H), 3.41 (d, J=13.5 Hz, 1/2 H), 3.31-3.28 m, 1 H), 3.13 (d, 1=14.2 Hz, 1/2 H), 3.04 (d, J=14.2 Hz, 1/2 H), 3.04 (d, J=14.2 Hz, 1/2 H), 2.92 (d, J=14 Hz, 1/2 H), 2.73 (d, J=14 Hz, 1/2 H), 2.54 ( d, J=13.8 Hz, 1 H), 2.30 ( br. d, J=13 Hz), 2.15,2.09 (2 s, 3 H), 2.00-1.95 (m, 1/2 H), 1.65-1.49 (m, 2 H), 1.37 (dt, J=4, 12.8 Hz, 1/2 H), 1.17-1.10 (m, 3 H).
Step D:
H
A solution of the intermediate dl from the previous step (2.0 g, 4.65 mmol) concentrated hydrochloric acid (25 mL) and ethanol (25 3 0 mL) was refluxed for 3 hours and was evaporated to dryness. The residue was neutralized by ammonium hydroxide and extracted by dichloromethane, and then was purified by Si02 flash column eluting vvith 1:10:90 NH40H:Me0H:CHC13 to yield the product (0.72 g, 61%). lH NMR (CD3OD, 400MHz) δ 8.88 (d, J=2 Hz, 1 H), 7.21 (d, J=2 Hz, 1 H), 4.20-4.07 (m, 2 H), 3.28 (br. d, 1 H), 3.06 (d, JAB=14 Hz, 1 H), 2.97 - 339 - LV 11525 (d, JBA=14 Hz, 1 H), 2.92-2.80 (md, 1 H), 2.61-2.57 (m, 2 H), 2.21-2.16 (br. d, 1 H), 1.66-1.40 (m, 3 H), 1.20 (t, J=7.3 Hz, 3 H). FAB-MS calc. for C12H18N2O2S : 254 ; Found 255 (M+H)
Step E:
To a stirred solution of the intermediate from the previous step (163 mg, 0.642 mmol), Intermediate 1 (250 mg, 0.642 mmol) and HOBT (87 mg, 0.642 mmol) in dichloromethane (20 mL) was added EDC (247 mg, 1.28 mmol) at 0°C. The reaction mixture was stirred ovemight and allowed to warm to room temperature. The solution was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate; then filtered and concentrated. Purification by MPLC eluting with 60% ethyl acetate in hexane provided the desired compound (285 mg, 71%). FAB-MS calc. for C32H43N5O6S : 625 ; Found 626 (M+H); 526 (M+-Boc(100)).
Step F:
-340-
Hydrogen chloride gas was bubbled into a solution of the intermediate from the previous step (270 mg, 0.43 mmol) in ethyl acetate (10 mL) at 0°C until it was saturated. The reaction was stirred for 30 minūtes, and evaporated to remove the ethyl acetate to afford the product 5 (226 mg, 93%). *H NMR (CD30D, 400MHz): 9.90 (d, J=2.2Hz, 4/5H), 9.5 (d, J=2.2 Hz, 1/5H), 8.48 (d, J=7.15,4/5H), 8.15 (d, 7.15,1/5H), 7.70 (d, J=2.2 Hz, 4/5H), 7.68 (d, J=2.2,1/5H), 7.55 (d, J=7.89 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06-6.95 (Μ, 1H), 3.94 (q, J=7.1 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 2.37 (d, J=14.9, 1H), 1.90 (d, 10 J=14.9,1H), 1.60(s, 6H), 1.07 (t, J=7.1 Hz, 3H), FAB-MS calc. for C27H35N5O4S : 525 ; Found 526 (M+H)
EXAMPLE C27A
Following the same procedures as in Example C27 and using the product d2 from step C, the tītie compound was prepared. FAB-MS calc. for C27H35N5O4S : 525 ; Found 526 (M+H)
The additional intermediates shown in Table CX were prepared with the corresponding alkylating aģents according to the above established procedure as exemplifīed in Example C27 steps A and B.
The final compounds were prepared according to Example C1 Steps D and E, using Intermediate 1. -341 - LV 11525
TABLE CX
Intermediate_Product
Intermediate Product
entry Y MF FAB-MS (M+l) MF FAB-MS (M+l) isomer 1 H3C. CH2- NfT 0 ch3 C14H22N2O3 267 C29H39N5O5 538 RS 2 2-thiazolylmethyl C12H18N2O2S 255 C27H35N5O4S 526 RS 3 4-thiazolylmethyl C12H18N2O2S 255 C27H35N5O4S 526 RS 4 5-thiazolylmethyl C12H18N2O2S 255 C27H35N5O4S 526 RS 5 (4-methyl-2- thiazolyl)methyl C13H20N2O2S 269 C28H37N5O4S 540 RS 6 (2-methyl-4- thiazolyl)methyl C13H20N2O2S 269 C28H37N5O4S 540 RS 7 (4-methyl-5- thiazolyl)methyl C13H20N2O2S 269 C28H37N5O4S 540 RS 8 (5-methyl-4- thiazolyl)methyl C13H20N2O2S 269 C28H37N5O4S 540 RS - 342-
A solution of the final product of Example C27 (50 mg), NaOH (3 N, 5 equiv.) in an mixture of ethanol/water (3:1,5 mL) was stirred at 60°C for two days. The reaction mixture as then evaporated in vacuo to remove ethanol. The residue was acidified by hydrochloric acid to pH=l and then evaporated to dryness. The white residue was purified by silica gel column eluting with 3/30/70 NH40H/Me0H/CHC13 to give the desired product (25 mg). FAB-MS calc. for C25H31N5O4S: 497 ; Found 498(M+H) E2CAMPLEC29
Boc n!c
Step A:
\=N
O
OH -343- LV 11525
The less polar (dl) intermediate from Example C27 step C (1.5 g, 3.48 mmol) was refluxed for 2 hours in ethanol (10 ml) and 5 N NaOH (3.5 mL). The mixture was then cooled to room temperature and slowly treated with 3 N HC1 to pH=l 1. To this stirred solution was added di-tert-butyl dicarbonate (1.52 g, 7 mmol) and stirred for two hours. The solution was acidified to pH 4 and then neutralized to pH 7 and extracted with ethyl acetate three times. The organic extracts were combined, dried, and concentrated to give white solid (810 mg).
Step B:
Boc ^isL
\^N
O OBn
To a solution of the intermediate from the last step (800 mg), benzyl alcohol (1.27 mL), and DMAP (30 mg) in dichloromethane (40 mL), was added EDC (935 mg, 4.9 mmol). The mixture was stirred at room temperature for three days, and was poured into dilute NaHC03 solution. It was extracted with ethyl acetate three times, and dried over MgS04. Evaporation and purifīcation by a flash column eluting with 20-40% ethyl acetate in hexane gavē the desired product.(145 mg).
Step C:
H
N
O OBn
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (140 mg) in ethyl acetate (20 mL) and HC1 gas at 0°C for 15 minūtes. After evaporation, the -344- residue was dissolved in dichloromethane and the solution was washed with NH40H. The organic layer was dried evaporated to give the product.
Step D:
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (140 mg, 0.443 mmol), Intermediate 1 (172 mg , 0.443 mmol), HOBT (60 mg.) and EDC (170 mg). Purification by MPLC, eluting with 80% ethyl acetate in hexane, provided the intermediate (210 mg).
Step E:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (12 mg, 0.018 mmol) and HC1 gas in ethyl acetate (3 mL) at 0°C for 10 minūtes. -345- LV 11525
Likevvise it is possible to prepare the compounds shown in Table CXa according to this example by reacting the intermediate from Example C29, Step A, with methylamine, ethylamine, ethanolamine, 3-aminopropanol or 2-(methylthio)ethylamine instead of benzyl alcohol in Step B, and using Intermediate 1 or Intermediate 3 in Step D. TABLE CXa
C=0 O .fL
X s
\^N entry 1 R1
H 2 3
4 5
H
X_ -CONHCH3 -CONHCH3 -CONHCH2CH3 -CONHCH2CH3 -C0NHCH2CH20H 5 -346- 5 -346- 10 15
-C0NHCH2CH20H
-CONH(CH2)30H
-CONH(CH2)30H -CONH(CH2)2SCH3 -CONH(CH2)2SCH3 20 EXAMPLE C30
25
Step A:
30 -347- LV 11525
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in Example C27 Step D (134 mg, 0.528 mmol), Intermediate 3 (200 mg , 0.528 mmol), HOBT (71 mg, 1 eq.), and EDC (200 mg, 2 eq.). Purification by MPLC, eluting with 60% ethyl acetate in hexane provided the intermediate (160 mg, 49%) FAB-MS calc. for C32H46N4O6S: 606 ; Found 607 (M+H)
Step B:
Prepared by the procedure described in Example Cl, Step C from the intermediate from the previous step (155 mg, 0.252 mmol) and HC1 gas in ethyl acetate (5 mL) at 0°C for 10 minūtes (142 mg, 96%). FAB-MS calc. for C27H38N4O4S: 506 ; Found 507 (M+H) EXAMPLEC31
-348- Step A:
Boc fL
NCO
To a stirred solution of the product from example 15 step A (2.00 g, 6..26 mmol) and DMF (3 drops) in benzene (20 mL) at 0°C, was added oxalyl chloride (0.89 g, 6.89 mmol) slowly. The reaction was stirred at 0°C for 10 minūtes and another 20 minūtes at room temperature. The reaction mixture was evaporated in vacuo to give the acyl chloride and it was used for the next reaction without further purification. To a stirred solution of the residue in acetone (20 mL) at 5 °C, was added sodium azide (1.22 g, 18.8 mmol) in water (3 mL) and the resulting mixture was stirred at room temperature for 30 minūtes. The reaction mixture was evaporated to remove acetone, and was diluted with vvater and extracted with ether. The ether extracts were combined and dried over MgS04. Filtration and evaporation gavē the crude azide and it was used without further purification. The resulting material was dissolved in toluene (70 mL) and was refluxed ovemight to give the isocyanate toluene solution. FAB-MS calc. for C18H24N2O3: 316; Found 217 (M+H-BOC(100)). $tep..g:
Boc
A solution of methanol (5 mL) and the solution obtained from the last step (15 mL out of 70 mL total, 1.3 mmol) was refluxed -349- LV 11525 ovemight. The reaction mixture was evaporated to give a vvhite solid (331 mg). FAB-MS calc. for C19H28N2O4: 348; Found 349 (M+H).
Step C: 5
HHCI
NHC02Me 10 15
To a solution of the intermediate from the previous step (271 mg) in ethyl acetate (15 mL) at 0°C, was bubbled hydrogen chloride gas until saturation occurred. The reaction was stirred for 30 minūtes, until TLC analysis indicated that the reaction was complete. The solution was then concentrated to remove the ethyl acetate to afford the product (284 mg). FAB-MS calc. for C14H20N2O2: 248; Found 249 (M+H)
Step D:
Prepared by the procedure described in Example Cl, Step D from the intermediate prepared in the previous step (0.284 g, 1 mmol), 30 Intermediate 1 (0.388 g, 1 mmol), HOBT (1 eq.), N-methyl morpholine (1 eq.), and EDC (1.5 eq.). Purification by MPLC, eluting with 60% ethyl acetate in hexane, provided the intermediate (0.35 g). FAB-MS calc. for C34H45N5O6: 619; Found 620 (M+H) 5 -350-
Step E: 10 15
To a solution of the intermediate from the previous step (200 mg, mmol) in ethyl acetate (10 mL) at 0°C, was bubbled hydrogen chloride gas until saturation occurred. The reaction was stirred for 30 minūtes, and then concentrated to remove the ethyl acetate to afford the product (158mg). FAB-MS calc. for C29H37N5O4: 519; Found 520 (M+H) 20 25
F.YAMPLE C32 H
Step A:
30 -351- LV 11525
To a stirred suspension of the intermediate obtained in Example C2, step C (HC1 salt, 2.51 g, 5.34 mmol), N-Boc-p-amino-P-Me-butyric acid (1.16g, 1 equiv.), NMM (0.6 mL, 1 equiv.) and DMAP (33 mg,0.05 equiv.) in dichloromethane (30 mL), was added EDC (1.55 g, 1.5 equiv.) in several portions. The reaction mixture quickly became clear and it was stirred for 3 hours and was worked up by diluting it with dichloromethane and washing with 3 N HC1, brine, and saturated sodium bicarbonate solution. The organic layer was dried over MgS04, evaporated and purified by silica gel column chromatography, eluting with 60% ethyl acetate in hexane to give the desired compound (3.40 g, 100%). FAB-MScalc.forC36H48N406:632; Found 633 (M+H)
To a stirred solution of the intermediate from the previous step (3.28 g, 5.18 mmol) in ethyl acetate (30 mL) at 0°C, was bubbled HC1 gas until it was saturated. The reaction was stirred for 10 minūtes, and was evaporated to dryness. The residue was dissolved in dichloromethane, and to which ether was added. The solid vvhich formed was collected by filtration, and it was air dried and left under high vacuum ovemight to give the product (2.44g, 83%). FAB-MS calc. for C31H40N4O4: 532; Found 533 (M+H)
Similarly the follovving compounds were prepared according to the same procedure as described above, but using different Boc protected amino acids which were subsequently deprotected as described above.
-352- TABLE CXI H
entry R11 MF FAB-MS (M+l) 1 D-Ala- C29H36N4O4 505 2 L-Ala- C29H36N4O4 505 3 β-Ala- C29H36N4O4 505 4 DL-a-Me-Ser- C30H38N4O5 535 5 C30H36N4O4 517 0 6 C33H42N4O4 559 0 7 D-Pro- C31H38N4O4 531 8 N-Me-Aib- C31H40N4O4 533 -353- LV 11525 FXAMPLE C33
To a stirred solution of the product from Example C32 (808 mg, 1.42 mmol), (R)-glyceraldehyde acetonide (923 mg, 5 equiv.) and sodium acetate (582 mg, 5 equiv.) in methanol (15 mL) at 0°C, was slowly added sodium cyanoborohydride (134 mg, 1.5 equiv.) and the resulting mixture was stirred at room temperature ovemight. The mixture was evaporated to remove methanol and partitioned between sodium bicarbonate solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic extracts were dried over magnesium sulfate and purified by a silica gel column, eluting with 5-10% methanol in dichloromethane to give the product (835 mg, 91%) FAB-MS calc. for C37H50N4O6: 646; Found 647 (M+H) EXAMPLE C34
OH
To a solution of the product from Example C33 (367 mg, 0.566 mmol) in methanol (10 mL) was added hydrochloric acid (3 N, 1 -354- mL) and the resulting mixture was stirred at room temperature for one day. The reaction mixture was evaporated in vacuo, and toluene was added and evaporated in vacuo again to remove the residual water to give the product (350 mg, 99%). FAB-MS calc. for C34H46N4O6: 606; 5 Found 607 (M+H) EXAMPLE C35
Additional benzyl substituted intermediates and products as shown in Table CXII were prepared according to procedures described in Example C1 Steps A and B using appropriately substituted benzyl halides in the alkylation step. Functional groups changes as needed were made at 2 0 the intermediate Step B stage to convert as needed cyano groups to carboxamides, esters and tetrazoles, nitro groups to amines and acetylamines and esters to acids (at step D) according to Standard literature procedures. 30 -355- LV 11525
TABLE CXII: ADDTTIONAL EXAMPLES -355- LV 11525
Intermediate Product entry R12 MF MF isomer 15 FAB-MS (M+l) FAB-MS (M+l) 1 o-cyano- CI6H20N2O2 C31H37N5O4 dl 273 544 d2 2 m-cyano- CI6H20N2O2 C31H37N5O4 dl 273 544 d2 3 p-cyano- CI6H20N2O2 C31H37N5O4 dl 273 544 d2 4 P-NH20C- C16H22N2O3 C31H37N5O4 RS 291 562 5 p-Et02C- CI8H25NO4 C33H42N4O6 dl 320 591 d2 6 P-H02C- C31H38N4O6 dl 563 d2 7 p-{ 1 H-tetrazole-5- CI6H21N5O2 C31H38N8O4 RS yi) 316 587 8 m-NH20C- C16H22N2O3 C31H37N5O4 RS 291 562 9 m-Et02C- CI8H25NO4 C33H42N4O6 dl 320 591 d2 10 m-H02C- C31H38N4O6 dl 563 d2 - 356- 11 m-{ 1 H-tetrazole-5- CI6H21N5O2 C31H38N8O4 RS yi) 316 587 12 0-NH2OC- CI6H22N2O3 C31H37N5O4 RS 291 562 13 o-Et02C- CI8H25NO4 C33H42N4O6 dl 320 591 d2 14 0-HO2C- C31H38N4O6 dl 563 d2 15 o-(lH-tetrazole-5- CI6H21N5O2 C31H38N8O4 RS yi 316 587 16 p-AcNH- C17H24N2O3 C32H41N5O5 RS 305 576 17 m-AcNH- C17H24N2O3 C32H41N5O5 RS 305 576
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammai being treated for any of the indications with the compounds of the invention indicated above. Likevvise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present phaimaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defīned by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. -357- LV 11525 WHATIS CLAIMEDIS: 1. A compound of the formula: Η Η O R, I. I II /4
Rļ—p-N-C-A-N C=0 Rs
I
Formula I wherein: Rļ is selected from the group consisting of: 15 Ci-ClO alkyl, aryl, aryl(Ci-C6 alkyl), (C3-C7 cycloalkyl)(Cl-C6 alkyl)-, (C1-C5 alkyl)-K-(Cļ-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Ci-C5 alkyl)-, and (C3-C7 cycloalkyl)(Co-C5 alkyl)-K-(Cļ-C5 alkyl)-, where K is 0, S(0)m, N(R2)C(0), C(0)N(R2), 0C(0), C(0)0, -CR2=CR2-, or -C=C-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, 20 pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a, 1 to 3 of 0R2a or C(0)0R2a, and aryl may be further substituted by 1 to 3 of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of 0R2, methylenedioxy, -S(0)mR2, 1 to 2 of-CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, 25 -C(0)N(R2)(R2), -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl, or -N(R2)S02R2; R2 is selected from: hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl, and where two Cļ-C6 alkyl groups are present on one atom, they may be 3 0 optionally joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR3a; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; -358- R3 is selected from: hydrogen, -(CH2)rphenyl, -(CH2)rnaphthyl, -C3-C7 cycloalkyl, where the phenyl, naphthyl and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: Cļ-C6 alkyl, halogen, -OR2, -NHSO2CF3, 5 -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r (Re), -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)!OC(0)R6, -(CH2)iC(0)R2, -(CH2)rC(0)R6, -(CH2)iC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-10 (CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)OR6,-(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), 15 -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2, -(CH2)rC0NHC(0)R6, 2 0 -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, .(CH2)rC0NHS02N(R2)R2), -(CH2)rC0NHS02N(R2)R6), -(CH2)rN(R2)S02N(R2)R6), -(CH2)rN(R6)S02N(R2)R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; 25 R3a is hydrogen, or Cļ-C6 alkyl optionally substituted by hydroxyl; W is selected from the group consisting of: hydrogen, -CN, -C(0)0R8, -C(0)0R2, -C(0)0(CH2)laryl, -C(0)N(R2)(R2)i -C(0)N(R2)(R8). -C(0)N(R2)(CH2)1 aryl, -CH2N(R2)C(0)R8 3 0 -CH2N(R2)C(0)(CH2)iaiyl, -(CH2)rOR2, -CH(OH)R2, -CH(OH)(CH2)iaryl, -C(0)R2, -C(0)(CH2)l aryl, lH-tetrazol-5-yl, 5-amino-l, 2, 4-oxadiazol-3-yl, and 5-methyl-l, 2, 4-oxadiazol-3-yl, where Rs is hydrogen, C1-C6 alkyl, or Cļ-C6 alkyl substituted by OR2, C(0)0R2, CON(R2)(R2), N(R2)C(0)R2, -359- LV 11525 N(R2)C(0)N(R2)(R2), and aryl is phenyl, pyridyl, or lH-tetrazol-5- yi; X is selected from the group consisting of: hydrogen, -ON, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taiyl, -(CH2)qN(R2)S02(CH2)taryl, -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)q0C(0)N(R2)(CH2)taryl, -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)2jļR2, and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substituted by ί to 2 Cj-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, carboxylate Cļ-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2), -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from the group consisting of: hydrogen, Cļ-ClO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cļ-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing 0, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, OC, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substituted by 1 -360- to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; with the proviso that at least one of R3, W, X, and Y are other than hydrogen; R4 and R5 are independently hydrogen, C1-C6 alkyl, substituted Cl-Ce alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-Cio alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, C1-C6 alkoxycarbonyl, S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)dLa(CH2)e- where La is C(R2)2, O, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defīned above; A is: or — (CH2)x-C-(CH2)— R7a z—(CH2)x-C-(CH2)y- R7a where x and y are independently 0, 1,2 or 3; Z is N-R6a or O, where R6a is hydrogen or C1-C6 alkyl; R6 is hydrogen, C1-C6 alkyl, or (CH2)varyl, wherein the alkyl and (CH2)v groups may be optionally substituted by 1-2 0(R2), S(0)mR2» lH-tetrazol-5-yl, C(0)OR2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2).and wherein aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-l-yl, benzimidazol-2-yl, triazolinone-yl optional!y substituted with Cl-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; R7 and R7a are independently hydrogen, Cļ-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2» C(0)0(Cl-C6 alkyl), -361 - LV 11525 C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms; 5 or R7 and R7a can be joined to one another to form a C3-C7 cycloalkyl; with the proviso that if R3, X or Y is unsubstituted phenyl, W is hydrogen, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a ar® other than unsubstituted Cļ-C6 alkyl; 1 is 0, 1 or 2; 10 m is 0, 1, or 2; n is 1, 2, or 3; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, or 3; t is 0, 1, 2, or 3; v is 0, 1, or 2 ; 15 and pharmaceutically acceptable salts and individual diastereomers thereof. 20 25 2. A compound of the formula: Η Η O r. II II ,4 Rļ—p-N-C-A-N C=0 R5 Μ-χ R3 γ
Formula AI wherein:
Rl is selected from the group consisting of: 30 C1-C10 alkyl, aryl, aryl(Cl-C6 alkyl), (C3-C7 cycloalkyl)(Cl-C6 alkyl)-, (C1-C5 alkyl)-K-(Cl-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Cl-C5 alkyl)-, and (C3-C7 cycloalkyl)(C0-C5 alkyl)-K-(Cl-C5 alkyl)-, where K is O, S(0)m» N(R2)C(0), C(0)N(R2), OC(O), C(0)0, -CR2=CR2-, or -OC-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and -362- R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a> 1 to 3 of OR2a or C(0)0R2a» and aryl may be further substituted by 1 to 3 of Cl-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0)mR2, 1 to 2 of-CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl, or -N(R2)S02R2; R2 is selected from: hydrogen, Cļ-C6 alkyl, and C3-C7 cycloalkyl, and where two Cļ-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring, optionaIly including oxygen, sulfur or NR3a; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; R3 is selected from: hydrogen, -(CH2)rphenyl, -(CH2)rnaphthyl, -Cl-ClO alkyl, -C3-C7 cycloalkyl, where the phenyl, naphthyl and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR2, -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6). -(CH2)r (R6). -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)OR2, -(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)OR2, -(CH2)rN(R6)C(0)0R6,-(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), -(CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, -(CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6,-(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6,-(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2, -(CH2)rCONHC(0)R6, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, _(CH2)rC0NHS02N(R2)(R2),-(CH2)rC0NHS02N(R2)(R6), -363- LV 11525 -(CH2)rN(R2)S02N(R2)R6), -(CH2)rN(R6)S02N((R2)(R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; W is selected from the group consisting of: -CN, -C(0)0R8, -C(0)0R2, -C(0)0(CH2)laryl, -C(0)N(R2)(R2); -C(0)N(R2)(R8), -C(0)N(R2)(CH2)1 aryl, -CH2N(R2)C(0)R8 -CH2N(R2)C(0)(CH2)laryl, -(CH2)rOR2, -CH(OH)R2, , -CH(OH)(CH2)iaryl, -C(0)R2, -C(0)(CH2)l aryl, lH-tetrazol-5-yl, 5-amino-l, 2,4-oxadiazol-3-yl, and 5-methyl-l, 2,4-oxadiazol-3-yl, where R8 is hydrogen, Cl-C6 alkyl, or Ci-C6 alkyl substituted by OR2, C(0)0R2, CON(R2)(R2), N(R2)C(0)R2, N(R2)C(0)N(R2)(R2), and aryl is phenyl, pyridyl, or lH-tetrazol-5- yi; X is selected from: hydrogen, -C=N, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S02(CH2)taryl, -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)q0C(0)N(R2)(CH2)taryl, -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substituted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2)i -C(0)0R2,1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from: hydrogen, Ci-ClO alkyl, -(CH2)taryl, -364- -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Ci-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing 0, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, OC, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; R4 and R5 are independently hydrogen, C1-C6 alkyl, substituted Ci-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-ClO alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, C1-C6 alkoxycarbonyl, S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)dLa(CH2)e- where La is C(R2)2,0, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defined above; A is: ^7 ^7 — (CH2)x-C-(CH2)— or —2-(CH2)x-C-(CH2)— R7a R7a where x and y are independently 0,1,2 or 3; Z is N-R6a or O, where R6a is hydrogen or C1-C6 alkyl; R6 is hydrogen, C1-C6 alkyl, or (CH2)varyl, wherein the alkyl and (CH2)v groups may be optionally substituted by 1-2 0(R2), S(0)mR2, lH-tetrazol-5-yl, C(0)OR2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2),and wherein aryl is phenyl, pyridyl, lH-tetrazol- -365- LV 11525 5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-l-yl, benzimidazol-2-yl, triazolinone-yl optionally substituted with Ci-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; R7 and R7a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2» C(0)0(Cl-C6 alkyl), C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms; or R7 and R7a can be joined to one another to form a C3-C7 cycloalkyl; 1 is 0,1 or 2; mis 0, 1, or2; n is 1, 2, or 3; q is 0, 1, 2, 3, or 4; r is 0,1,2, or 3; tis 0,1,2, or3; v is 0,1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof. -366- 3. The compound of Claim 2 vvherein:
Rl is selected from the group consisting of:
Cl-ClO alkyl, aryl (C1-C4 alkyl)-, C3-C6 cycloalkyl (C1-C4 alkyl)-, 5 (C1-C4 alkyl)-K-(Ci-C2 alkyl)-, aryl (C0-C2 alkyl)-K-(Cl-C2 alkyl)-, and (C3-C7 cycloalkyl)(Co-C2 alkyl)-K-(Cl-C2 alkyl)-, where K is 0, S(0)m, 0C(0), C(0)0 and the alkyl groups may be further substituted by 1 to 7 halogen, S(0)mR2» 1 to 3 0R2 or C(0)0R2 and aryl is phenyl, naphthyl, indolyl, pyridyl, benzothienyl, or benzofuranyl which may be 1° further substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 0R2, S(0)mR2 or C(0)OR2; R2 is hydrogen, Cļ-C6 alkyl, or C3-C7 cycloalkyl and where two Cļ-C6 alkyl groups are present on one atom they may be optionally joined to 15 form a C4-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3 is hydrogen or phenyl optionally substituted in the ortho position by a C1-C6 alkyl group, -NHSO2CF3, -(CH2)r (lH-tetrazol-5-yl), -(CH2)rC(0)0R2, (CH2)rC(0)N(R2)(R6); 20 R3a is hydrogen, or C1-C4 alkyl; W is -CN, -C(0)0R2, -C(0)N(R2)(R2), -C(0)N(R2)(CH2)l phenyl, lH-tetrazol-5-yl, or -(CH2)rOR2; 25 X is hydrogen, -(CH2)qC(0)N(R2)(R6), or -(CH2)qC(0)0R2; Y is hydrogen, C1-C8 alkyl, -(CH2)t phenyl, -(CH2)t pyridyl, or -(CH2)tthiazolyl; R4 and R5 are independently hydrogen, C1-C6 alkyl, or substituted Cl-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(0)m (Cļ-C6 alkyl) or phenyl; 30 -367- LV 11525 R6 is hydrogen, or Cl-C6 alkyl; Ais:
R7a (CH2)*-C— where x is 0, or 1; R7 and R7a are independently hydrogen C\-C6 alkyl, trifluoromethyl, phenyl, substituted Cl-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0(Ci-C6 alkyl), C5-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independently be joined to one of R4 or R5 to form alkylene bridges between the termiņai nitrogen and the alkyl portion of R7 or R7a groups to form 5 or 6 membered rings; or R7 and R7a can be joined to one another to form a C3 cycloalkyl; 1 is 0 or 1; n is 2; m is 0,1, or 2; ris 0,1,2 or 3; q is 0 or 1 t is 0 or 1; and pharmaceutically acceptable salts and individual diastereomers thereof. -368- 4. The compound of Claim 2 of the formula: Η Η O r,
Ri—ļ-N-C-A-N C=0 R5
R3
Formula Alb wherein: Rļ is selected from the group consisting of: Ci-CļO alkyl, aryl (C1-C3 alkyl)-, and aryl (Co-Cl alkyl)-K-(Ci-C2 alkyl)-, where K is O or S(0)m and the aryl is phenyl, pyridyl, naphthyl, or indolyl which are optionally substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)m R2 orC(0)OR2; R2 is hydrogen, Cļ-C6 alkyl, or C3-C7 cycloalkyl and where two Cļ-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3 is hydrogen or phenyl optionally substituted in the ortho position by a C1-C3 alkyl group, (CH2)r(lH-tetrazol-5-yl) or (CH2)rC(0)0R2; R3a is hydrogen, or C1-C4 alkyl; W is -CN, -C(0)0R2, or -C(0)N(R2)R2); X is hydrogen or C(0)0R2; Y is hydrogen, benzyl, picoyl, or thiazolylmethyl; R4 and R5 are independently hydrogen, C1-C3 alkyl, substituted C1-C3 alkyl where the substituents may be 1 to 2 hydroxyl; -369- LV 11525
Ais:
5 vvhere x is 0, or 1; λ 0 R7 and R7a are independently hydrogen orCļ-C4 alkyl; m is 0, 1, or 2; r is 0,1, or 2; 15 and pharmaceutically acceptable salts and individual diastereomers thereof. 5. The stereospecifically defined compound of Claim 2 2o of the formula:
Η Η O
Rļ—ļ^N-C-A-N C=0
25 wherein Rļ, R3, R4, R5, A, W, X, Y, and n are as defined in Claim 2. 30 -370- 6. The compound of Claim 2 vvhich is selected from the group consisting of:
CN -371- LV 11525
H? V -^cXNh2c=0 oN ļ U H /N Cn
c=o χζ
-372-
and pharmaceutically acceptable salts and individual diastereomers thereof. LV 11525 A compound of the formula: - 373 -7. Η Η O R. i il ,4 R1
-N-C-A-N C=0
(CH^S Μ-χ
Formula BI ίο vvherein:
Rl is selected from the group consisting of:
Cl-ClO alkyl, aryl, aryl(Cl-C6 alkyl), (C3-C7 cycloalkyl)(Ci-C6 alkyl)-, (C1-C5 alkyl)-K-(Cl-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Cl-C5 alkyl)-, 15 and (C3-C7 cycloalkyl)(C0-C5 alkyl)-K-(Cl-C5 alkyl)-, where K is O, S(0)m, N(R2)C(0), C(0)N(R2), OC(O), C(0)0, -CR2=CR2-, or -GC-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a> 1 20 to 3 of OR2a or C(0)0R2a, and aryl may be further substituted by 1 to 3 of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0)mR2,1 to 2 of -CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2)» -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl, or -N(R2)S02R2; 25 R2 is selected from: hydrogen, Cļ-C6 alkyl, and C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR3a, where R3a is hydrogen, or C1-C6 alkyl, 3 0 optionally substituted by hydroxyl; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; R3 is selected from: -(CH2)rphenyh -(CH2)rnaphthyl, -C3-C7 cycloalkyl, and the phenyl, naphthyl and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group -374- consisting of: Cl-C6 alkyl, halogen, -OR2, -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r (R6), -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 5 -(CH2)rN(R2)C(0)R6,-(CH2)rN(R6)C(0)R2,-(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6, ,(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, 1 ū -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6),-(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, _(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)OR6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, 15 -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2 , -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, .(CH2)tC0NHS02N(R2)(R2), -(CH2)rC0NHS02N(R2)(R6), -(CH2)rN(R2)S02N(R2)(R6), -(CH2)rN(R6)S02N(R2)(R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; 20 R3a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; X is selected from: hydrogen, -ChN, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S02(CH2)taryl, 25 -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl,-(CH2)q0C(0)N(R2)(CH2)taryl, 3 0 -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substituted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, -375- LV 11525 carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groupš which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2), -C(0)0R2,1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from: hydrogen, C1-C10 alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing 0, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m> C(0)NR2, CH=CH, OC, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lovver alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, 1 to 2 -N(R2)(R2)»-C(0)0R2, -C(0)N(R2)(R2), nitro, -NHC(0)R2,cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; R4 and R5 are independently hydrogen, C1-C6 alkyl, substituted Cļ-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-CiO alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, C1-C6 alkoxycarbonyl, S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)dLa(CH2)e- where La is C(R2)2» 0> S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defmed above; A is: or — (CH2)x-C-(CH2)y- ^7a -Z-(CH2)x-C-(CH2)r ^7a -376- where x and y are independently 0,1, 2 or 3; Z is N-R6a or O, where R6a is hydrogen or Cl-C6 alkyl; R6 is hydrogen, C\-C6 alkyl, or (CH2)varyl, wherein the alkyl and (CH2)v groups may be optionally substituted by 1-2 0(R2), S(0)mR2, lH-tetrazol-5-yl, C(0)0R2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2)>and wherein aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-l-yl, oxadiazolyl, benzimidazol-2-yl, triazolinone-yl, optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; R7 and R7a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)OR2» C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms; or R7 and R7a can be joined to one another to form a C3-C7 cycloalkyl; with the proviso that if R3 is unsubstituted phenyl, X is hydrogen, Y is hydrogen, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a are other than unsubstituted C1-C6 alkyl; m is 0,1, or 2; n is 1, 2, or 3; q is 0, 1, 2, 3 or 4; ris 0, 1,2, or 3; t is 0,1,2, or3; v is 0,1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof. -377- LV 11525 8. The compound of Claim 7 wherein:
Rl is selected from the group consisting of:
Ci-ClO alkyl, aryl (C1-C4 alkyl)-, C3-C6 cycloalkyl (C1-C4 alkyl)-, 5 (C1-C4 alkyl)-K-(Ci-C2 alkyl)-, aryl (C0-C2 alkyl)-K-(Ci-C2 alkyl)-, and (C3-C7 cycloalkyl)(Co-C2 alkyl)-K-(Cl-C2 alkyl)-, where K is O, S(0)m, 0C(0), or C(0)0, and the alkyl groups may be fiirther substituted by 1 to 7 halogen, S(0)mR2> 1 to 3 OR2 or C(0)0R2, and aryl is phenyl, naphthyl, indolyl, pyridyl, benzimidazolyl, azaindoleyl, 10 benzothienyl or benzofuranyl which may be further substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 -OR2, -S(0)mR2, or -C(0)0R2; R2 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to 15 form a C4-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3 is phenyl which is optionally substituted by 1 to 2 Cļ-C6 alkyl groups, 1 to 2 halogen, or 1 to 2 -OR2, and vvhich may be further substituted in the ortho position by a substitutent selected from the group 20 consisting of: -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r (R6), -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, _(CH2)iC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 2 5 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2,-(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6f· -(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, 3 0 -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, .(CH2)rOC(0)N(R2)(R6)>-(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, .(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -378- -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2, -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, -(CH2)rC0NHS02N(R2)R2), -(CH2)rCONHSC>2N(R2)R6), -(CH2)rN(R2)S02N(R2)R6), -(CH2)rN(R6)S02N(R2)R6), -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl,(-CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02(CH2)taryl -(CH2)qN(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally substituted by hydroxyl, carboxyl, CONH2, S(0)mCH3, carboxylate Cl-C4 alkyl esters, or tetrazole and the aryl which is phenyl, naphthyl, pyridyl or l-H-tetrazolyl may be optionally substituted by 1 to 2 halogen, 1 to 2 -OR2, -CONH2, -C(0)0R2, 1 to 3 C1-C4 alkyl, -S(0)mR2, or 1H-tetrazole-5-yl; Y is selected from: hydrogen, Cļ-C8 alkyl, (CH2)taryl, -(CH2)q(C5-C6 cycloalkyl), -(CH2)q-K-(Ci-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR2, or S), and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is O or S(0)m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and the aryl which is phenyl, naphthyl, pyridyl, l-H-tetrazolyl, thiazolyI, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiopheneyl is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2,1 to 2 -N(R2)(R2), -C(0)OR2, -C(0)N(R2)(R2), cyano, 1 to 2 C1-C4 alkyl, benzyl, -S(0)mR2, or lH-tetrazol-5-yl; -379- LV 11525 R4 and R5 are independently hydrogen, C1-C6 alkyl,or substituted Cl-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(0)m (C1-C6 alkyl) or phenyl; R6 is H, C1-C6 alkyl, or (CH2)varyl, wherein the (CH2)v and alkyl groups may be optionally substituted by 1-2 0(R2), S(0)mR2, C(0)0R2, C(0)N(R2)(R2) or S02N(R2)(R2), N(R2)C(0)N(R2)(R2), wherein the aryl group could be phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optiorially substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; A is: (CH2)x—C— 7a
R where x is 0, or 1; R7 and R7a are independently hydrogen, C1-C6 alkyl, triflucromethyl, phenyl, substituted C1-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0R2, C5-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2); or R7 and R7a can independendy be joined to one of R4 or R5 to form alkylene bridges between the termiņai nitrogen and the alkyl portion of R7 or R7a groups to form 5 or 6 membered rings; or R7 and R7a can be joined to one another to form a C3 cycloalkyl; with the proviso that if R3 is unsubstituted phenyl, X is hydrogen, Y is hydrogen, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a are other than unsubstituted C1-C6 alkyl; n is 2; mis 0, 1, or2; r is 0,1,2, or 3; q is 0, 1, 2, or 3; t is 0, 1,2, or 3; v is 0, 1, or 2, -380- and pharmaceutically acceptable salts and individual diastereomers thereof. 9. The compound of Claim 7 of the formula:
I
Formula BIb wherein: Rļ is selected from the group consisting of: Cl-ClO alkyl, aryl (C1-C3 alkyl)-, (C3-C7 cycloalkyl)(Cl-C3 alkyl)-, and aryl (Co-Cļ alkyl)-K-(Ci-C2 alkyl)-, where K is O or S(0)m and aryl is specifically phenyl, pyridyl, naphthyl, indolyl, azaindolyl, or benzimidazolyl which is optionally substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)m R2, or C(0)0R2; R2 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cyclič ring optionally including oxygen, sulfur or NR3a; R3 is phenyl optionally substituted by 1 to 2 Cļ-C6 alkyl groups, 1 to 2 halogen or 1 to 2 OR2, and which may be further substituted in the ortho position by a substitutent selected from the group consisting of: -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r (R6). -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2)f -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2, - 381 - LV 11525 -(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)OR2, -(CH2)rN(R6)C(0)0R6, -(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2),-(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6,-(CH2)rN(R2)S02R2,-(CH2)rN(R6)S02R2, 5 CH2)rN(R6)S02R6,-(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rSC>2N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, -(CH2)rS(0)mR6, and 10 -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, 15 -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)q N(R2)S02(CH2)taryl, -(CH2)q N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qN(R2)C(0)0R2, -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)q0C(0)R2, 20 -(CH2)q0C(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally substituted by hydroxyl, carboxyl, -CONH2, -S(0)mCH3, carboxylate C1-C4 alkyl esters or tetrazole and aryl is phenyl, napthyl or pyridyl which may be further substituted by 1-2 halogen, 1 to 2 OR2, C(0)0R2, 25 1 to 3 C1-C4 alkyl, S(0)mR2» or lH-tetrazole-5-yl; Y is selected from: hydrogen, C1-C8 alkyl, (CH2)taryl, -(CH2)qC5-C7 cycloalkyl, -(CH2)q-K-(Cļ-C6 alkyl), -(CH2)q-K-(CH2)taryl, and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is S(0)m and where the 3 0 alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and aryl is specifically phenyl, napthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl which may be optionally substituted -382- by 1 to 2 halogen, 1 to 2 OR2, 1 to 2 -N(R2)(R2), -CO(OR2), 1 to 2 Cl-C4 alkyl, S(0)mR2i or lH-tetrazol-5-yl; R4 and R5 are independently hydrogen, C1-C4 alkyl, substituted C1-C3 alkyl where the substituents may be 1 to 2 hydroxyl; R6 is hydrogen, Cļ-C6 alkyl or (CH2)varyl, wherein the C1-C6 alkyl and the (CH2)yaryl groups may be optionally substituted by 1-2 0(R2), S(0)mR2, C(0)0R2, C(0)N(R2)(R2) or SC>2N(R2)(R2), N(R2)C(0)N(R2)(R2)> wherein aryl is specifically phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl; A is: (CH2)x—C — 7a
R where x is 0, or 1; R7 and R7a are independently hydrogen, C1-C2 alkyl, phenyl, substituted C1-C6 alkyl wherein the substitutent is imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2; or R7 and R7a can be independently be joined to one another to form a C3 cycloalkyl; with the proviso that if R3 is unsubstituted phenyl, X is hydrogen, Y is hydrogen, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a are other than unsubstituted C1-C2 alkyl; m is 0, 1, or 2; ris 0,1,2, or 3; q is 0,1, 2, or3; t is 0,1,2, or3; v is 0, 1, or 2; and pharmaceutically acceptable salts and individual diastereomers thereof. -383- LV 11525 10.
The compound of Claim 7 of the formula:
Η H Ri—c-n-c-a-n: I II C=0 O I r4 r5
X Y R3 Formula BIc wherein: Rļ is selected from the group consisting of:
rT"V MeO-rļ- ch2-
-384- or their regioisomers vvhere not specified; R2 is hydrogen, Cļ-C6 alkyl, or C3-C7 cycloalkyl and where two Cļ-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3 is phenyl optionally substituted in the ortho position with a substitutent selected from the group consisting of: -NHSO2CF3, -(CH2)rOR6, -(CH2)r (R6). -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)r0C(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)iC(0)N(R2)(R6). -(CH2)rN(R2)C(0)R2 -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2, -(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6,-(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6), (CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2),(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC0NHS02R6,-(CH2)rC0NHS02R2, -(CH2)rS(0)mR6, and -(CH2)rS(0)mR2; R3a is hydrogen, or C1-C4 alkyl; -385- LV 11525 X is selected from the group consisting of: hydrogen, O O O O CH3 ^0'CH° Ar® A0-^ch3 Λ0Αοη
-386- Υ is selected from the group consisting of: hydrogen, Cļ-C8 alkyl, (CH2)taryl, -(CH2)q C5-C7 cycloalkyl, -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, or -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl) where K is S(0)m and where the alkyl groups may be 5 optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate Cl-C4 alkyl esters or lH-tetrazole-5-yl, and where aryl is specifically phenyl, naphthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyiimidinyl, or imidazolyl, which may be optionally substituted by 1 to 2 halogen, 1 to 2 OR2, CO(OR2), 1 to 2 10 C1-C4 alkyl, S(0)mR2 or lH-tetrazol-5-yl; ch3 h3cv.ch3 A is selected from the group consisting of: H3Vch3 h3c ch3 ch3 { 15
?—Λ* V'S CH, H,C. ,CH,
NH
20
νγ W R4 and R5 are independently selected from the group consisting of: 25 — H — CH3 — CH2CH3 z^YCH3 ^^γ0Η20Η
OH OH R6 is hydrogen, Cļ-C6 alkyl or (CH2)varyl wherein the alkyl and (CH2)v groups may be optionally substituted by halogen, OR2, N(R2)(R2). C3-C6 cycloalkyl, lH-tetrazol-5-yl, C(0)0R2, 3o C(0)N(R2)(R2). S02N(R2)(R2) or N(R2)C(0)N(R2)(R2), wherein aryl is selected from the following aromatic groups and their regioisomers: -387- -387- LV 11525 n=n 1 -O. H ^Vo n-n H * H N—J 'S" S-N , N=\ -*> f Λ A O-N v> N-N , H —— // O-N , where the aromatic groups are optionally substituted with C1-C2 alkyl, -N(R2)(R2)? οr hydroxy; mis 0, l,or2; ris 0,1,2, or3; q is 0 or 1; t is 0 or 1; v is 0 or 1; and pharmaceutically acceptable salts and individual diastereomers thereof. - 388- 11. The stereospecifically defined compound of Claim 7 of the formula: Η Η O r, R,—J-N-C-A-N C=0 R5
(CHjjS Μ-χ r3 y vvherein Rļ, R3, R4, R5, A, X, Y, and n are as defined in Claim 7. 12. The compound of Claim 7 which is selected from the group consisting of:
-389- LV 11525
cis cis do. trans dļ. trans d2
cis dļ. cis d2. trans dļ. trans d2 -390-
-391 - LV 11525
IZ
cis dļ. cis d2 -392-
and their pharmaceutically acceptable salts and individual diastereomers thereof where not othenvise specified. -393- LV 11525 13. A compound of the formula: Η Η O ,r4
Rļ-t-N—C-A—N
c=° V ļ **5
(CH^N \-Ļx
Y
Formula CI wherein: R] is selected from the group consisting of:
Ci-Cio alkyl, aryl, aryl(Cl-C6 alkyl), (C3-C7 cycloalkyl)(Ci-C6 alkyl)-, (C1-C5 alkyl)-K-(Cl-C5 alkyl)-, aryl(Co-C5 alkyl)-K-(Ci-C5 alkyl)-, and (C3-C7 cycloalkyl)(C0-C5 alkyl)-K-(Ci-C5 alkyl)-, where K is O, S(0)m* N(R2)C(0), C(0)N(R2), OC(O), C(0)0, -CR2=CR2-, or -OC-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and R2 and alkyl may be further substituted by 1 to 9 halogen, S(0)mR2a> 1 to 3 of OR2a or C(0)0R2a> and aryl may be further substituted by 1 to 3 of C1-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0)mR2, 1 to 2 of-CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -lH-tetrazol-5-yl, -S02N(R2)(R2), -N(R2)S02 phenyl, or -N(R2)S02R2; R2 is selected from: hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring, optionally including oxygen, sulfur or NR3a, where R3a is hydrogen, or C1-C6 alkyl, optionally substituted by hydroxyl; R2a is hydrogen, or C1-C6 alkyl optionally substituted by hydroxyl; X is selected from: hydrogen, -C=N, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S02(CH2)taiylf -(CH2)qN(R2)S02R2,-(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -394- -(CH2)qN(R2)C(0)N(R2)(R2),-(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)q0C(0)N(R2)(CH2)taryl, -(CH2)q0C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2, (CH2)q and (CH2)t group may be optionally substituted by 1 to 2 C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, CONH2, S(0)mCH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -CON(R2)(R2), -C(0)0R2,1 to 3 C1-C4 alkyl, -S(0)mR2, or lH-tetrazol-5-yl; Y is selected from: hydrogen, Ci-ClO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR2, S), and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0)m, C(0)NR2, CH=CH, C=C, N(R2)C(0), C(0)NR2, C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups may be optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or carboxylate C1-C4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C1-C4 alkyl, -S(0)mR2, °r lH-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; -395- LV 11525 R4 and R5 are independently hydrogen, C1-C6 alkyl, or substituted Cļ-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-CiO alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenyloxy, 2-furyl, C1-C6 alkoxycarbonyl, S(0)m(Cl-C6 alkyl), or R4 and R5 may be taken together to form -(CH2)d-La(CH2)e- where La is -C(R2)2-» O, S(0)m or N(R2), d and e are independently 1 to 3 and R2 is as defīned above; A is:
*j*7 ļV — (CH2)X—C - (CH2)y— or -z- (CH2)x-C - (CH2)— R7a R7a where x and y are independently 0, 1, 2 or 3; Z is N-R6a or 0, where R6a is hydrogen or C1-C6 alkyl; R7 and R7a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, or substituted Cl-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2> C(0)OR2, C3-C7 cycloalkyl, N(R2)(R2), C(0)N(R2)(R2), or R7 and R7a may independently be joined to one or both of R4 and R5 groups to form an alkylene bridge between the termiņai nitrogen and the alkyl portion of the R7 or R7a groups, vvherein the bridge contains 1 to 5 carbons atoms, or R7 and R7a can be joined to one another to form C3-C7 cycloalkyl; with the proviso that if X or Y is unsubstituted phenyl, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a are other than unsubstituted C1-C6 alkyl; m is 0,1, or 2; n is 1,2, or 3; q is 0, 1, 2, 3, or 4; t is 0, 1,2, or 3; and pharmaceutically acceptable salts and individual diastereomers thereof. -396- 14. The compound of Claim 13 wherein: Rļ is selected from the group consisting of:
Ci-Cio alkyl, aryl (C1-C4 alkyl)-, C3-C6 cycloalkyl (C1-C4 alkyl)-, (C1-C4 alkyl)-K-(Cl-C2 alkyl)-, aryl (C0-C2 alkyl)-K-(Cl-C2 alkyl)-, 5 and (C3-C7 cycloalkyl)(C()-C2 alkyl)-K-(Ci-C2 alkyl)-, where K is O, S(0)m. 0C(0), or C(0)0, and the alkyl groups may be further substituted by 1 to 7 halogen, S(0)mR2> 1 to 3 OR2 or C(0)0R2, and aryl is phenyl, naphthyl, indolyl, pyridyl, benzimidazolyl, azaindoleyl, benzothienyl or benzofuranyl which may be further substituted by 1-2 10 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 -OR2, -S(0)mR2, or -C(0)0R2; R2 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C4-C7 cyclic ring optionally including oxygen, sulfur or NR3a; 15 R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)C(0)0R2, -(CH2)qN(R2)S02(CH2)taryl, -(CH2)qN(R2)S02R2, 2 ū -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2),-(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taiyl, -(CH2)q0C(0)R2, -(CH2)qOC(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally 25 substituted by hydroxyl, carboxyl, CONH2, S(0)mCH3, carboxylate Ci-C4 alkyl esters, or tetrazole, and aryl is phenyl, naphthyl, pyridyl or 1-H-tetrazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 -OR2, -CONH2, -C(0)0R2,1 to 3 C1-C4 alkyl, -S(0)mR2, or 1H-tetrazole-5-yl; 30 Y is selected from: hydrogen, C1-C8 alkyl, (CH2)taryl, -(CH2)q(C5-C6 cycloalkyl), -(CH2)q-K-(Ci-C6 alkyl), -(CH2)q-K-(CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR2, or S), and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is O or S(0)m and -397- LV 11525 where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and aryl is phenyl, naphthyl, pyridyl, l-H-tetrazolyl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, 5 isoxazolyl, or thiopheneyl which is optionally substituted by 1 to 3 halogen, 1 to 3 -OR2, -C(0)0R2, -C(0)N(R2)(R2)> cyano, 1 to 2 C1-C4 alkyl, benzyl, -S(0)mR2, or lH-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; !0 R4 and R5 are independently hydrogen, C1-C6 alkyl, or substituted Cļ-C6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(0)m (C1-C6 alkyl) or phenyl; A is: 15 p7 (CH2)x-C- ^7a wherex is 0, or 1; 20 R7 and R7a are independently hydrogen Cļ-C6 alkyl, trifluoromethyl, phenyl, substituted Cļ-C6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, C(0)0R2, C5-C7 cycloa!kyl, -N(R2)(R2), -C(0)N(R2)(R2); or R7 and R7a can independently be joined to one of R4 or R5 to form alkylene bridges 25 between the termiņai nitrogen and the alkyl portion of R7 or R7a groups to form 5 or 6 membered rings; or R7 and R7a can be jcined to one another to form a C3 cycloalkyl; with the proviso that if X or Y is unsubstituted phenyl, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a are other than unsubstituted C1-C6 alkyl; 30 n is 2; m is 0, 1, or2; q is 0, 1, 2, or 3; t is 0, 1, 2, or 3; and pharmaceutically acceptable salts and individual diastereomers thereof. -398- 15. The compound of Claim 13 of the formula: I 11 N_, c=o ° Rs i
wherein: Rļ is selected from the group consisting of: Cl-ClO alkyl, aryl (C1-C3 alkyl)-, (C3-C7 cycloalkyl)(Ci-C3 alkyl)-, and aryl (Co-Cl alkyl)-K-(Cl-C2 alkyl)-, where K is O or S(0)m and the aryl is phenyl, pyridyl, naphthyl, indolyl, azaindolyl, or benzimidazolyl which is optionally substituted by 1-2 C1-C4 alkyl, 1 to 2 halogen, 1 to 2 OR2, S(0)m R2, or C(0)0R2; R2 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom they may be optionally joined to form a C5-C7 cyclic ring optionally including oxygen, sulfur or NR3a; R3a is hydrogen, or C1-C4 alkyl; X is selected from: hydrogen, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)q N(R2)S02(CH2)taiyl, -(CH2)q N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2),-(CH2)qC(0)N(R2)(R2), -(CH2)qN(R2)C(0)0R2, -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)taryl, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)taryl, -(CH2)qS(0)mR2, and -(CH2)qS(0)m(CH2)taryl, where an R2 group may be optionally substituted by hydroxyl, carboxyl, -CONH2, -S(0)mCH3, carboxylate C1-C4 alkyl esters or tetrazole and aryl is phenyl, naphthyl or pyridyl which may be further substituted by 1-2 halogen, 1 to 2 OR2, C(0)0R2, 1 to 3 C1-C4 alkyl, S(0)mR2, or lH-tetrazole-5-yl; -399- LV 11525 Y is selected from: hydrogen, Cl-C8 alkyl, (CH2)taryl, -(CH2)q C5-C7 cycloa!kyl, -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-(CH2)taryl, and -(CH2)q-K-(CH2)t (C5-C6 cycloalkyl), where K is S(0)m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH2, carboxylate C1-C4 alkyl esters or lH-tetrazole-5-yl and aryl is phenyl, napthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 OR2,1 to 2 -N(R2)(R2), CO(OR2), 1 to 2 C1-C4 alkyl, S(0)mR2, or lH-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; R4 and R5 are independently hydrogen, C1-C4 alkyl, or substituted Ci-C3 alkyl where the substituents may be 1 to 2 hydroxyl; A is (CH2)x—C— ^7a where x is 0, or 1; R7 and R7a are independently hydrogen, C1-C6 alkyl, phenyl, substituted C1-C6 alky wherein the substitutent is imidixolyI, phenyl, indolyl, p-hydroxyphenyl, OR2, S(0)mR2, or R7 and R7a may be joined to one another to form a C3 cycloalkyl; with the proviso that if X or Y is unsubstituted phenyl, R4 is hydrogen, and R5 is hydrogen, then R7 and R7a are other than unsubstituted Cļ-Q) alkyl; m is 0,1, or 2; q is 0,1,2, or 3; tīs 0,1,2, or 3; and pharmaceutically acceptable salts and individual diastereomers thereof. -400- 16. The compound of Claim 13 of the formula: Η H 1 Λ -A-N" Rs
Ri—Č—N-C- II o
C=0 I M
X Y Formula CIc wherein: Rl is selected from the group consisting of: -^CH2‘ /CH2- (1-2)F- '
N H
MeO />- ,CH,-
I
or their regioisomers where not specified; -401 - LV 11525
X is selected from the group consisting of: hydrogen, O O O O A0'CH3 .Et
CH, ^o-^ch3
-402- Υ is selected from the group consisting of: hydrogen, -402-
HaC CH3 CHo-
EtOsC -H-
tetrazole- CH2-
1-3 halogen-M-CH2- ks^CH2-
‘N -CH2-
N rCH9-
/
‘N
N H ^iAch2-
H3C—^ 4ch2
‘N
N
N N-
t8- (V H3C\N^Tl ^ J-S- <' jfCH2-'^ch3 N-^/CH3 <' ^CHj-
.-J
f 3-CH. N- /CH2- S'Ī CH3 ch3 2*
N—. f tCH2-H
HaC-Hf ļcH2-H N^, </ j-CH2- μ ch3 or their regioisomers whereof where not specifīed, with the proviso that if X is hydrogen, Y is other than hydrogen; -403 LV 11525 A is selected from the group consisting of: XH3 h3c. xh3
h3cwch3h3c ch3 ch3 r T
v χγ xy w vV
H,C
VV W R4 and R5 are independently selected from the group consisting of: —H —CH3 —CH2CH3 ^γΟΗ2ΟΗ
OH OH and pharmaceutically acceptable salts and individual diastereomers thereof. 17. The stereospecifically defīned compound of Claim 13 of the formula: Η Η O r. = 1 II ,4
N-C-A-N C=0 (0Η2ίί
—X Y wherein Rļ, R4, R5, A, X, Y, and n are as defīned in Claim 13. -404- 18. The compound of Claim 13 which is selected from the group consisting of:
-405- 15 LV 11525
Η Η 10
Ν Η OEt
Η Η kN
I ΝΗο
c=o ο NL
S Ο
Ο OEt Ί 20 25
30 -406-
-407-LV 11525
-408-
thereof where not othenvise specifīed. 19. A composition useful for increasing the endogenous production or release of grovvth hormone in a human or an animal which comprises an inert carrier and an effective amount of a compound of Claini 1. 20. A composition useful for increasing the endogenous production or release of grovvth hormone in a human or an animal which comprises an inert carrier, an effective amount of a compound of Claim 1, and an additional growth hormone secretagogue. 21. The composition of Claim 20 wherein the additional grovvth hormone secretagogue is selected from the group consisting of: grovvth hormone releasing peptide GHRP-6; grovvth hormone releasing peptide GHRP-2; grovvth hormone releasing peptide GHRP-1; B-HT920; grovvth hormone releasing factor; an analog of grovvth hormone releasing factor; IGF-1 and IGF-2. 22. A composition useful for the treatment of osteoporosis vvhich comprises a combination of a bisphosphonate compound and a compound of Claim 1. 23. The composition of Claim 22 vvherein the bisphosphonate compound is alendronate. -409- LV 11525 24. Use of a compound of Claim 1 for manufacturing a medicament providing for increasing Ievels of endogenous growth hormone in human or an animal. 25. Use of a compound of Claim 1 for manufacturing a medicament providing for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock. 26. Use of a compound of Claim 1 for manufacturing a medicament providing for treating or preventing a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuāls with a depressed T4/T8 celi ratio; hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; obesity; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or bums. 27. Use of a combination of a bisphosphonate compound and compound of Claim 1 for manufacturing a medicament providing for the treatment of osteoporosis. 28. The use of Claim 27 wherein the bisphosphonate compound is alendronate. 29. A process for the preparation of a compound of Claim 1 which comprises reacting a compound of the formula:
H H R1 —N-H C=0
W (CH2)ny Μ-χ R3 y -410- with a compound of the formula: 0 R II .4 9 L T. 0 1 0 1 > 1 z or HO-C-A-N 15 R5 Rs 5 6 to give a compound of the formula: where Rļ, R3, R4, R5, A, W, X, Y and n are as defīned in Claim 1 and L is a protecting group which is subsequently removed if present and salts 30 are formed if desired. 30. A compound which is:
or a pharmaceutically acceptable salt thereof. 20 ,R4
Η Η O I II —N-C-A-N c=o r5 Η Η O l —N-C-A-N C=0 Rs 25
Rl
or R1
-411 - -411 - LV 11525 31. A compound which is:
32. A pharmaceutical composition which comprises an inert carrier and an effective amount of the compound of Claim 30. LV 11525
(54) Tītie: PIPERIDINES, PYRROLIDINES AND HEXAHYDRO-1H-AZEPINES PROMOTE RELEASE OF GRO\VTH HORMONE (57) Abstract The present invention is directed to cērtam piperidine, pyrrolidine, and hexahydro-lH-azepine compounds of general structural formula (I) wherein Rj, R3, Ra, R5, A, W, X, Y, and n are as defined herein. These compounds promote the release of growth hormone in humāns and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humāns, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone. Grovvth hormone releasing compositions containing such compounds as the active ingredient thereof are also disclosed. R1 Η Η O r, N-C-A-N Rs
c=o I X (CH2)nΜ-χ
W (I)
Rc

Claims (28)

LV 11525 Izgudrojuma formula 1. Savienojums ar formulu (I): V Ϊ 9 P* Rn—F-N-C-A-N C=0 Rs (CH2i!llyw H-* r3 y (I) kurā: Rļ ņemts no rindas: Ci-ioalkilgrupa, arilgrupa, aril-Ci-ealkīlgrupa, C^cikloalkil-Cļ-ealkilgrupa, Ci.5alkil-K-Ci-5alkilgrupa, aril-Co-5alkil-K-Ci.5alkilgrupa, C3.7 ciklo-alkil-C0.5alkil-K-Ci-5alkilgrupa, kur K ir -O-, -S(0)m-, -N(R2)C(0)-, -OC(O)-, -C(0)0-, -CR2=CR2- vai -OC-, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, azaindolilgrupa, piridilgrupa, benzotienilgrupa, benzofuranilgrupa, tiazolilgrupa, benzimidazolilgrupa, pie tam R2 un alkilgrupas neobligāti aizvietotas ar 1 - 9 halogēna atomiem, -S(0)mR2a, 1 - 3 -OR2a vai -C(0)0R2a grupām, bet arilgrupa neobligāti aizvietota ar 1 - 3 Ci-6alkilgrupām, 1 - 3 halogēna atomiem, 1 - 2 -OR2 grupām vai metilēndioksigrupām vai -S(0)mR2 grupām; 1 - 2 trifluormetilgrupām vai trifluormetoksigrupām vai nitrogrupām vai grupām: -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -S02N(R2)(R2), -N(R2)S02-C6H5, -N(R2)S02R2 vai 1H-tetrazol-5-ilgrupām; R2 ņemts no rindas: ūdeņraža atoms, Ci-ealkilgrupa, C3-7cikloalkilgrupa, pie tam , ja pie viena atoma pievienotas divas Ci-ealkilgrupas, tās neobligāti savienotas, veidojot C3-eciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; 1 R2a ir ūdeņraža atoms, Ci^alkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; R3 ņemts no rindas: ūdeņraža atoms, -(CH2)rfenilgrupa, -(CH2)r-naftilgrupa, C3-7 cikloalkilgrupa, pie tam fenilgrupa, naftilgrupa un C^cikte neobligāti aizvietoti ar 1 - 3 aizvietotājiem no rindas: Ci-ealkilgrupa, halogēna atoms, -OR2, -NHSO2CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH2)r(R6), -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)r0C(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)-C(0)R2, -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6( -(CH2)rN(R2)C(0)0R2, -(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)r-N(R6)C(0)0R6, -(CH2)rN(R2)C(0)N(R2)(R6), -(CH2)rN(R2)C(0)N(R2)(R2), -(CH2)rN(R6)C(0)N(R2)(R6). -(CH2)rN(R2)S02R6, -(CH2)rN(R2)S02R2, -(CH2)rN(R6)S02R2, -(CH2)rN(R6)S02R6, -(CH2)r0C(0)N(R2)(R6), -(CH2)r OC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2), -(CH2)r S02NHC(0)R6, *(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)r S02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2),C(0)NHC(0)R2l -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6, -(CH2)rC0NHS02R2, -(CH2)rCONHS02N(R2)(R2), -(CH2)rC0NHS02N(R2)(R6), '(CH2)rN(R2)S02N(R2)(R6), -(CH2)rN(R6)S02N(R2)(R6), -(CH2)rS(0)mR6 un -(CH2)fS(0)mR2; R3a ir ūdeņraža atoms, Ci-6alkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; W ņemts no rindas: ūdeņraža atoms, ciāngrupa, -C(0)0R8, -C(0)0R2, -C(6)0(CH2)i-arilgrupa, -C(0)N(R2)(R2), -C(0)N(R2)(R8), -C(0)N(R2)(CH2)r arilgrupa, -CH2N(R2)C(0)R8, -CH2N(R2)C(0)(CH2)rarilgrupa, -(CH2)rOR2, -CH(OH)R2, -CH(OH)(CH2),-arilgrupa, -C(0)R2, -C(0)(CH2),-ahlgrupa, 1H-tetrazol-5-ilgrupa, 5-amino-1,2,4-oksadiazol-3-ilgrupa, 5-metil-1,2,4-oksadiazol-3-ilgrupa, kur R8 ir ūdeņraža atoms, Ci^alkilgrupa, kas neobligāti aizvietota ar grupām: -OR2, -C(0)0R2, -CON(R2)(R2), -N(R2)C(0)R2, -N(R2)C(0)N(R2)(R2), bet arilgrupa ir fenilgrupa, piridilgrupa vai 1 H-tetrazol-5- ilgrupa; X ņemts no rindas: ūdeņraža atoms, ciāngrupa, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)rarilgrupa, -(CH2)qN(R2)S02(CH2)rarilgrupa, -(CH2)q-N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)t-arilgrupa, -(CH2)qN(R2)-C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)rarilgrupa, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)t-arilgrupa, -(CH2)qOR2, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)rarilgrupa, -(CH2)q0C(0)N(R2)(CH2)rarilgrupa, -(CH2)qO-C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)rarilgrupa, -(CH2)qN(R2)-C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2 un -(CH2)qS(0)m(CH2)r arilgrupa, kur R2, (CH2)q un (CH2)t neobligāti aizvietoti ar 1 - 2 Ci^alkilgrupām, hidroksilgrupu, C^alkoksigrupu, karboksilgrupu, -CONH2, -SiOjmCHa, -C(0)0-Ci^alkilgrupu, 1H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa, naftilgrupa, piridilgrupa, tiazolilgrupa vai 1H-tetrazol-5-ilgrupa, kuras neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1-3 grupām -OR2, -C(0)N(R2)(R2), -C(0)0R2, 1 - 3 Ci-4alkilgrupām, -S(0)mR2 vai 1 H-tetrazol-5-ilgrupu; 2 LV 11525 Y ņemts no rindas: ūdeņraža atoms, CMoalkilgrupa, -(Chfejt-arilgrupa, -(CH2)cr C^cikloalkilgrupa, -{C^Jg-K-C^alkilgrupa, -(CH2)q-K-(CH2)rarilgrupa1 -(CH2)q-K-(CH2)rC3-7Cikloalkilgrupa, kas cikloalkilgrupā satur -O-, >NR2 vai -S-, -(CH2)q-K-(CH2)rC3-7cikloalkilgrupaI kur K ir -O-, -S(0)m-, -C(0)NR2-, -CH=CH-, -OC-, -N(R2)C(0)-, -C(0)NR2-, -C(0)0- vai -OC(O)-, bet alkilgrupas, R2, (CH2)q un (CH2)t neobligāti aizvietotas ar CMalkilgrupu, hidroksilgrupu, Ci^alkoksigrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci^alkilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridilgrupa, 1H-tetrazol-5-ilgrupa, tiazolilgrupa, imidazolilgrupa, indolilgrupa, pirimidinilgrupa, tiadiazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa, tiofenilgrupa, hinolinilgrupa, pirazinilgrupa vai izotiazolilgrupa, kas neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 -OR2 grupām, -C(0)0R2, -C(0)N(R2)(R2), nitrogrupu, ciāngrupu, benzilgrupu, 1 - 3 Ci^alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu, ar tādu noteikumu, ka vismaz viens no aizvietotājiem R3, W, X vai Y nav ūdeņraža atoms; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci.6alkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1 - 3 hidroksilgrupām, 1 - 3 Ci-i0alkan-oiloksigrupām, 1 - 3 Ci^alkoksigrupām, fenilgrupu, fenoksigrupu, 2-furilgrupu, Ci.6alkoksikarbonilgrupu, -SiOjm-Cļ-ealkilgrupu, vai arī R4 un R5 abi kopā var veidot grupu -(CH2)d-La-(CH2)e-, kurā La ir -C(R2)2-, -0-, -S(0)m- vai -N(R2)-, bet d un e neatkarīgi viens no otra ir 1 - 3, un R2 nozīmes ir jau minētās; Air: — (CH2)x-C-(CH2)r ^7a vai — Z-(CH2)x-C-(CH2)y— ^7a kur x un y neatkarīgi viens no otra ir 0, 1, 2 vai 3; Z ir -N(R6a)- vai -O-, kur R6a ir ūdeņraža atoms vai Ci_6alkilgrupa; R6 ir ūdeņraža atoms, Ci^alkilgrupa vai -(CH2)v-arilgrupa, kur alkilgrupas un (CH2)v grupas neobligāti aizvietotas ar 1 - 2 -0(R2), -S(0)mR2, 1 H-tetrazol-5-ilgrupu, -C(0)0R2i -C(0)N(R2)(R2), -S02N(R2)(R2) vai -N(R2)C(0)N(R2)(R2), pie tam arilgrupa ir fenilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, triazolilgrupa, imidazolilgrupa, tiazolilgrupa, pirazolilgrupa, tiadiazolilgrupa, imidazolon-1-ilgrupa, benzimidazol-2-ilgrupa, triazolinonilgrupa, kas neobligāti aizvietotas ar Ci.6alkilgrupu, C3-6 cikloalkilgrupu, aminogrupu vai hidroksilgrupu; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, Ci^alkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2, -S(0)mR2, -C(0)0-Ci. 6alkilgrupu, C3-7cikloalkilgrupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arī R7 un R7a 3 neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5, veidojot alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, pie tam tiltiņš var saturēt no 1 līdz 5 oglekļa atomus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3.7cikloalkilgrupu, ar tādu noteikumu, ka tad, kad R3, X vai Y ir neaizvietota fenilgrupa, bet W, R4 un R5 ir ūdeņraža atoms, R7 un R7a nav neaizvietota Cļ^alkilgrupa; I ir 0, 1 vai 2; m ir 0, 1 vai 2; n ir 1,2 vai 3; q ir 0, 1,2, 3 vai 4; r ir 0, 1, 2 vai 3; tirO, 1,2 vai 3; v ir 0, 1 vai 2; kā arī šī savienojuma farmaceitiski pieņemamās sālis.Formula 1. A compound of Formula (I): V Ϊ 9 P * Rn-FNCAN C = O R 8 (CH 2 Cl 2 H 3 R 3 y (I) in which R 1 is selected from C 1-10 alkyl, aryl, aryl-C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl-C 1 -C 6 alkyl, C 1-5 alkyl-K-C 1-5 alkyl, aryl-Co-5 alkyl-K-C 1-5 alkyl, C 3-7 cycloalkyl-C 0-5 alkyl-K-C 1 -5alkyl, where K is -O-, -S (O) m-, -N (R2) C (O) -, -OC (O) -, -C (O) 0-, -CR2 = CR2- or -OC-, but aryl is selected from phenyl, naphthyl, indolyl, azaindolyl, pyridyl, benzothienyl, benzofuranyl, thiazolyl, benzimidazolyl; - 3 for -OR2a or -C (O) 0R2a groups, but aryl is optionally substituted with 1 to 3 C1-6 alkyl groups, 1-3 halogens, 1 to 2 -OR2 groups or methylenedioxy groups, or -S (O) mR2 groups; 2 trifluoromethyl groups or trifluoromethoxy groups or nitro groups or groups: -N (R 2) C (O) (R 2), -C (O) 0 R 2, -C (O) N (R 2) (R 2), -SO 2 N (R2) (R2), -N (R2) SO2-C6H5, -N (R2) SO2R2 or 1H-tetrazol-5-yl; R2 is taken from the group consisting of: hydrogen, C1-6alkyl, C3-7cycloalkyl, where two C1-6alkyl groups are attached to one atom, they are optionally bonded to form a C3-alkyl optionally containing an oxygen or sulfur atom or a group >NR3a; 1 R 2a is hydrogen, C 1-6 alkyl optionally substituted by hydroxy; R3 is selected from the group consisting of: hydrogen, - (CH2) rphenyl, - (CH2) r-naphthyl, C3-7 cycloalkyl, phenyl, naphthyl and C1-4 optionally substituted with 1 to 3 substituents selected from the group consisting of C1-6alkyl; halogen, -OR2, -NHSO2CF3, - (CH2) rOR6, - (CH2) rN (R2) (R6), - (CH2) r (R6), - (CH2) rC (O) 0R2, - (CH2) rC (O) 0R6, - (CH2) rC (O) R2, - (CH2) rC (O) R6, - (CH2) rC (O) R2, - (CH2) rC (O) R6, - (CH2) rC (O) N (R 2) (R 2), - (CH 2) r C (O) N (R 2) (R 6), - (CH 2) r N (R 2) -C (O) R 2, - (CH 2) r N (R 2) ) C (O) R 6, - (CH 2) r N (R 6) C (O) R 2, - (CH 2) r N (R 6) C (O) R 6 (- (CH 2) r N (R 2) C (O) 0 R 2, - (CH 2) r N (R 2) C (O) 0 R 6, - (CH 2) r N (R 6) C (O) 0 R 2, - (CH 2) r N (R 6) C (O) 0 R 6, - (CH 2) r N (R 2) C (0) N (R 2) (R 6), - (CH 2) r N (R 2) C (O) N (R 2) (R 2), - (CH 2) r N (R 6) C (O) N (R 2) (R 6) - (CH2) rN (R2) SO2R6, - (CH2) rN (R2) SO2R2, - (CH2) rN (R6) SO2R2, - (CH2) rN (R6) SO2R6, - (CH2) r0C (O) N (R 2) (R 6), - (CH 2) r OC (O) N (R 2) (R 2), - (CH 2) r SO 2 N (R 2) (R 6), - (CH 2) r SO 2 N (R 2) (R 2) - ( CH 2) r SO 2 NHC (O) R 6, * (CH 2) r SO 2 NHC (O) R 2, - (CH 2) r SO 2 NHC (O) 0 R 6, - (CH 2) r SO 2 NHC (O) 0 R 2, - (CH 2) r C (O) NHC ( 0) NR2, - (CH2) rC (O) NHC (O) NR6, - (CH2), C (O) NHC (O) R 2l - (CH2) rC0NHC (O) R6, - (CH2) rCONHSO2R6, - (CH2) rCONHSO2R2, - (CH2) rCONHSO2N (R2) (R2), - (CH2) rC0NHSO2 (R2) (R6), (CH2) ) rN (R2) SO2N (R2) (R6), - (CH2) rN (R6) SO2N (R2) (R6), - (CH2) rS (O) mR6 and - (CH2) fS (O) mR2; R 3a is hydrogen, C 1-6 alkyl optionally substituted with hydroxy; W taken from the hydrogen atom, cyano, -C (O) 0R8, -C (O) 0R2, -C (6) 0 (CH2) i-aryl, -C (O) N (R2) (R2), -C (O) N (R2) (R8), -C (O) N (R2) (CH2) r aryl, -CH2N (R2) C (O) R8, -CH2N (R2) C (O) (CH2) ) Raryl, - (CH2) rOR2, -CH (OH) R2, -CH (OH) (CH2), - aryl, -C (O) R2, -C (O) (CH2), --hl, 1H-tetrazole -5-long group, 5-amino-1,2,4-oxadiazol-3-yl, 5-methyl-1,2,4-oxadiazol-3-yl, wherein R8 is hydrogen, C1-6 alkyl optionally substituted ar grupām: -OR2, -C (O) 0R2, -CON (R2) (R2), -N (R2) C (O) R2, -N (R2) C (O) N (R2) (R2), but aryl is phenyl, pyridyl or 1H-tetrazol-5-yl; X taken from hydrogen: cyano, - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) raryl, - (CH2) qN (R2) S02 (CH2) raryl, - (CH2) qN (R2) SO2R2, - (CH2) qN (R2) C (O) N (R2) (CH2) t -aryl, - (CH2) qN (R2) -C (O) ) N (R2) (R2), - (CH2) qC (O) N (R2) (R2), - (CH2) qC (O) N (R2) (CH2) raryl, - (CH2) qC (O) 0R2, - (CH2) qC (O) 0 (CH2) t -aryl, - (CH2) qOR2, - (CH2) qC (O) R2, - (CH2) qC (O) (CH2) raryl, - (CH2) ) q0C (O) N (R2) (CH2) raryl, - (CH2) qO-C (O) N (R2) (R2), - (CH2) qC (O) R2, - (CH2) qC (0) (CH2) raryl, - (CH2) qN (R2) -C (O) 0R2, - (CH2) qN (R2) SO2N (R2) (R2), - (CH2) qS (O) mR2 and - (CH2) qS (0) m (CH 2) r aryl, where R 2, (CH 2) q and (CH 2) t are optionally substituted with 1 to 2 C 1-6 alkyl, hydroxyl, C 1-4 alkoxy, carboxyl, -CONH 2, -SiOjmCHa, -C ( 0) 0-C 1-4 alkyl, 1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl optionally substituted with 1 to 3 halogens, 1-3 groups - OR2, -C (O) N (R2) (R2), -C (O) 0R2, 1-3C1-4alkyl, -S (O) mR2 or 1 H-tetrazol-5-yl; Taken from the series: hydrogen, CMoalkyl, - (Chfejt-aryl, - (CH2) cr C 1-4 cycloalkyl, - {C 1 -C 8 -C 1 -C 4 alkyl, - (CH 2) q K- (CH 2) raryl 1 - ( CH2) qK- (CH2) rC3-7Cycloalkyl containing cycloalkyl -O-, > NR2 or -S-, - (CH2) qK- (CH2) rC3-7cycloalkyl wherein K is -O-, -S (0) m-, -C (O) NR2-, -CH = CH-, -OC-, -N (R2) C (O) -, -C (O) NR2-, -C (O) 0-, or -OC (O) -, but alkyl, R2, (CH2) q and (CH2) t are optionally substituted with C1-4alkyl, hydroxy, C1-4alkoxy, carboxyl, -C (O) NH2, or -C (O) O-C1-4alkyl, wherein aryl is phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl optionally substituted with 1 to 3 halogens atoms, 1-3 -OR2 groups, -C (O) 0R2, -C (O) N (R2) (R2), nitro, cyano, benzyl, 1-3C1-4alkyl, -S (O) mR2v a 1 H-tetrazol-5-yl, provided that at least one of the substituents R 3, W, X or Y is not hydrogen; R4 and R5 are independently from each other hydrogen, C1-6alkyl, optionally substituted with 1-5 halogens, 1-3 hydroxyl groups, 1-3C 1-10 alkan-olefin groups, 1-3C1-6 alkoxy groups, phenyl, phenoxy, 2 -furyl, C 1-6 alkoxycarbonyl, -Si 0jm-C 1-6 alkyl, or R 4 and R 5 together may form a group - (CH 2) d -L- (CH 2) e - wherein La is -C (R 2) 2 -, - 0-, -S (O) m- or -N (R 2) -, but d and e are independently 1 to 3, and R 2 has the same meanings; Air: - (CH2) x-C- (CH2) r7-7a or - Z- (CH2) x-C- (CH2) y-? 7a wherein x and y are independently 0, 1, 2 or 3; Z is -N (R 6a) - or -O-, wherein R 6a is hydrogen or C 1-6 alkyl; R6 is hydrogen, C1-6alkyl or - (CH2) v-aryl, where alkyl and (CH2) v are optionally substituted with 1-22 (R2), -S (O) mR2, 1H-tetrazol-5 -yl, -C (O) 0R2i -C (O) N (R2) (R2), -SO2N (R2) (R2) or -N (R2) C (O) N (R2) (R2), in addition aryl is phenyl, pyridinyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolon-1-yl, benzimidazol-2-yl, triazolinonyl optionally substituted with C 1-6 alkyl, C 3-6 cycloalkyl , amino or hydroxy; R7 and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-6 alkyl optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S (O) mR2, -C (O) 0 -Ci. 6alkyl, C3-7cycloalkyl, -N (R2) (R2), -C (O) N (R2) (R2), or R7 and R7a3 are independently bonded to one or both R4 and R5 to form \ t alkylene bridges between the extreme nitrogen atom and the R7 and R7a alkyl moieties, wherein the bridge may contain from 1 to 5 carbon atoms, or R7 and R7a may be joined together to form a C3-7cycloalkyl group, provided that when R3 \ t , X or Y is unsubstituted phenyl but W, R4 and R5 are hydrogen, R7 and R7a are not unsubstituted C1-4 alkyl; I is 0, 1 or 2; m is 0, 1 or 2; n is 1,2 or 3; q is 0, 1,2, 3 or 4; r is 0, 1, 2 or 3; tirO, 1,2 or 3; v is 0, 1 or 2; as well as the pharmaceutically acceptable salt of this compound. 2. Savienojums ar formulu (AI):2. A compound of formula (AI): (AI) kurā: R1 ņemts no rindas: Cļ.ioalkilgrupa, arilgrupa, aril-C^alkilgrupa, C3.7cikloalkil-Ci^alkilgrupa, Ci_5alkil-K-Ci.5alkilgrupa, aril-Co-salkil-K-Ci-salkilgrupa, C3.7 cikloalkil-Co-5alkil-K-Ci.5alkilgrupa, kur K ir -O-, -S(0)m-, -N(R2)C(0)-, -C(0)N(R2)-, -OC(O)-, -C(0)0-, -CR2=CR2- vai -C=C-, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, azaindolilgrupa, piridinilgrupa, benzotienil-grupa, benzofuranilgrupa, tiazolilgrupa, benzimidazolilgrupa, pie tam R2 un alkilgrupas neobligāti aizvietotas ar 1 - 9 halogēna atomiem, -S(0)mR2a, 1-3 -OR2a vai -C(0)OR2a grupām, bet arilgrupa neobligāti aizvietota ar 1 - 3 Ci^alkilgrupām, 1-3 halogēna atomiem, 1-2 -OR2 grupām, metilēndioksigrupām vai -S(0)mR2 grupām, 1-2 trifluormetilgrupām vai trifluormetoksigrupām vai nitrogrupām vai grupām: -N(R2)C(0)(R2), -C(0)OR2i -C(0)N(R2)(R2), -S02N(R2)(R2), -N(R2)S02-C6H5i -N(R2)S02R2 vai 1 H-tetrazol-3-ilgrupām; 4 LV 11525 r2 ņemts no rindas: ūdeņraža atoms, Ci^alkilgrupa, C3-7Cikloalkilgrupa, pje tam , ja pie viena atoma pievienotas divas Ci^alkilgrupas, tās neobligāti savienotas, veidojot C^ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; _ . . . R2a ir ūdeņraža atoms, Ci-6alkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; R3 ņemts no rindas: ūdeņraža atoms, -(CH2)rfenilgrupa, -(Ch^jr-naftilgrupa, Ci-ioalkilgrupa, C3.7 cikloalkilgrupa, pie tam fenilgrupa, naftilgrupa un C3.7dkls neobligāti aizvietoti ar 1 - 3 aizvietotājiem no rindas: Ci-ealkilgrupa, halogēna atoms, -OR2, -NHS02CF3, -(CH2)rOR6, -(CH2)rN(R2)(R6)i -(CHžMRe). -(CH2)r-C(0)0R2, -(CH2)rC(0)0R6, -(CH2)rOC(0)R2, -(CH2)rOC(0)R6, -(CH2)r-C(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)r.N(R2)-C(0)R2, -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)C(0)R6, -(CH2)rN(R2)C(0)0R2, -(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)0R2, -(CH2)rN(R6)C(0)0R6, -(CH2)rN (R2)C(0)N (R2)(R6), -(CH2)rN(R2)C(0)- N(R2)(R2), -(0H2)rN(R6)C(0)N(R2)(R6), -(CH2)rN(R2)S02R6, -(CH2)rN(R2)-S02R2, -(CH2)rN(R6)S02R2, -(CH2)rN(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2), -(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2, -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6, -(CH2)rC0NHS02R2, -(CH2)rC0NHS02N(R2)(R2), -(CH2)rC0NHS02N(R2)(R6), -(CH2)rN(R2)S02N(R2)(R6), -(CH2)rN(R6)S02N(R2)(R6), -(CH2)rS(0)mR6 un -(CH2)rS(0)mR2; R3a ir ūdeņraža atoms vai C^alkilgrupa, neobligāti aizvietota ar hidroksilgrupu; W ņemts no rindas: ciāngrupa, -C(0)0R8, -C(0)0R2l -C(0)0(CH2)i-arilgrupa, -C(6)N(R2)(R2), -C(0)N(R2)(R8), -C(0)N(R2)(CH2)rarilgrupa, -CH2N(R2)- C(0)Re, -CH2N(R2)C(0)(CH2)i-arilgrupa, -(CH2)rOR2, -CH(OH)R2, -CH(OH)-(CH2)i-arilgrupa, -C(0)R2, -C(0)(CH2)i-arilgrupa, 1H-tetrazol-5-ilgrupa, 5-amino-1,2,4-oksadiazol-3-ilgrupa, S-metil-l.ž^-oksadiazol-S-ilgrupa, kur R8 ir ūdeņraža atoms, Ci-6alkilgrupa, kas neobligāti aizvietota ar grupām. -OR2, -C(0)0R2, -CON(R2)(R2), -N(R2)C(0)R2, -N(R2)C(0)N(R2)(R2), bet arilgrupa ir fenilgrupa, piridilgrupa vai 1H-tetrazol-5-ilgrupa; X ņemts no rindas: ūdeņraža atoms, ciāngrupa, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)t-arilgrupa, -(CH2)qN(R2)S02(CH2)t-arilgrupa, -(CH^-N(R2)S02R2i -(CH2)qN(R2)C(0)N(R2)(CH2)q-arilgrupa, -(CH2)qN(R2)C(0)-N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)t-adgrupa, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)rarilgrupa, -(CH2)qOR2, -(CH2)q0C(0)R2l -(CH2)q0C(0)(CH2)rarilgrupa, -(CH2)q0C(0)N(R2)(CH2)t-arilgrupa -(CH2)qO-C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)t-anlgrupa, <^2)^2)-C 0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)rr,R2 un -(CH2)qS(0)m(CH2)r arilgrupa, kur R2, (CH2)q un (CH2)t neobligāti aizvietoti ar 1 - 2 c^a,^'19l'uPa/J1’ hidroksilgrupu, CMalkoksigrupu, karboksilgrupu, -CONH2, -S(0)mūM3, -C(0)0-Ci-4alkilgrupu, 1H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa naftilgrupa, piridilgrupa, tiazolilgrupa vai 1H-tetrazol-5-ilgrupa, kuras neobligāti 5 aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 grupām -OR2, -C(0)N(R2)(R2), -C(0)0R2, 1 - 3 Ci-4alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; γ ņemts no rindas: ūdeņraža atoms, Ci-ioalkilgrupa, -(Chhjt-arilgrupa, -(Ch^V C3-7cikloalkilgrupa, -(CH2)q-K-Ci^aIkilgrupa, -(CH2)q-K-(CH2)t-arilgrupa, -(CH2)q-K-(CH2)t-C3-7cikloalkilgrupa, kas cikloalkilgrupā satur -O-, >NR2 vai -S-, -(CH2)q-K-(CH2)t-C3-7Cikloalkilgrupa, kur K ir -O-, -S(0)m-, -C(0)NR2-, -CH=CH-, -CsC-, -N(R2)C(0)-,. -C(0)NR2-, -C(0)0- vai -OC(O)-, bet alkilgrupas, R2, (CH2)q un (CH2)t neobligāti aizvietotas ar C^alkilgrupu, hidroksilgrupu, Ci^alkoksigrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci^alkilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, tiazolilgrupa, imidazolilgrupa, indolilgrupa, pirimidinilgrupa, tiadiazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa, tiofenilgrupa, hinolinilgrupa, pirazinilgrupa vai izotiazolilgrupa, kas neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 -OR2 grupām, -C(0)0R2, -C(0)N(R2)(R2), nitrogrupu, ciāngrupu, benzilgrupu, 1 - 3 Ci-*alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Cļ-ealkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1 - 3 hidroksilgrupām, 1 - 3 Ci-ioalkan-oiloksigrupām, 1-3 Ci-6alkoksigrupām, fenilgrupu, fenoksigrupu, 2-furilgrupu, Ci.6alkoksikarbonilgrupu, -SiOJm-Cļ-ealkilgrupu, vai arī R4 un R5 abi kopā var veidot grupu -(CH2)d-L.a-(CH2)e-, kurā La ir -C(R2)2-, -O-, -S(0)m- vai -N(R2)-, bet d un e neatkarīgi viens no otra ir 1 - 3, un R2 nozīmes ir jau minētās; Air: vai — (CH2)x-C-(CH2)jT ^7a 97 —Z-(CH2)x-C-(CH2)r ^7a kur x un y neatkarīgi viens no otra ir 0,1,2 vai 3; Z ir -N(R6a)- vai -O-, kur R6a ir ūdeņraža atoms vai Ci-6alkilgrupa; R6 ir ūdeņraža atoms, Ci.6alkilgrupa vai -(CH2)v-arilgrupa, kur alkilgrupas un (CH2)v grupas neobligāti aizvietotas ar 1 - 2 -0(R2), -S(0)mR2, 1 H-tetrazol-5-ilgrupu, -C(0)0R2, -C(0)N(R2)(R2), -S02N(R2)(R2) vai -N(R2)C(0)N(R2)(R2), pie tam arilgrupa ir fenilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, triazolilgrupa, imidazolilgrupa, tiazolilgrupa, pirazolilgrupa, tiadiazolilgrupa, imidazolon-1-ilgrupa, benzimidazol-2-ilgrupa, triazolinonilgrupa, kas neobligāti aizvietotas ar Ci_6alkilgrupu, C3.6 cikloalkilgrupu, aminogrupu vai hidroksilgrupu; R/ un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, C^ealkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, 6 LV 11525 fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2, -S(0)mR2l -C(0)0-Ci^alkilgrupu, C3-7Cikloalkilgrupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arī R7 un R7a neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5, veidojot alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, pie tam tiltiņš var saturēt no 1 līdz 5 oglekļa atomus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3.7cikloalkilgrupu. I ir 0,1 vai 2; m ir 0,1 vai 2; n ir 1, 2 vai 3; q ir 0, 1, 2, 3 vai 4; rirO, 1, 2 vai 3; t ir 0, 1, 2 vai 3; vir 0,1 vai 2; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuāli diastereomēri.(AI) wherein: R 1 is selected from the group consisting of C 1-10 alkyl, aryl, aryl C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-5 alkyl-K-C 1-5 alkyl, aryl-Co-salkyl-K-C 1-6 alkyl, C 3-7 cycloalkyl-Co-5-alkyl-K-C 1-5 alkyl wherein K and -O-, -S (O) m -, -N (R 2) C (O) -, -C (O) N (R 2) - -, -OC (O) -, -C (O) 0-, -CR 2 = CR 2 - or -C = C-, but aryl is taken from phenyl, naphthyl, indolyl, azaindolyl, pyridinyl, benzothienyl, benzofuranyl , thiazolyl, benzimidazolyl, furthermore R2 and alkyl are optionally substituted with 1 to 9 halogen atoms, -S (O) mR2a, 1-3 -OR2a or -C (O) OR2a, but aryl optionally substituted with 1 to 3 Ci ^ alkyl groups, 1-3 halogens, 1-2 -OR2 groups, methylenedioxy groups or -S (O) mR2 groups, 1-2 trifluoromethyl groups or trifluoromethoxy groups or nitro groups or groups: -N (R2) C (O) (R2) - C (O) OR2i -C (O) N (R2) (R2), -SO2N (R2) (R2), -N (R2) SO2-C6H5i -N (R2) SO2R2 or 1H-tetrazol-3-yl ; Taken from the series: hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, where two C 1-6 alkyl groups are attached to one atom, they are optionally bonded to form a C 1-8 ring optionally containing an oxygen or sulfur atom, or group >NR3a; _. . . R 2a is hydrogen, C 1-6 alkyl optionally substituted by hydroxy; R3 is selected from the group consisting of: hydrogen, - (CH2) rphenyl, - (CH3-naphthyl, C1-10alkyl, C3-7cycloalkyl, phenyl, naphthyl and C3-7 optionally substituted with 1 to 3 substituents from the row: C1-6alkyl, halogen, -OR2, -NHSO2CF3, - (CH2) rOR6, - (CH2) rN (R2) (R6) i - (CH2 NMR) - (CH2) rC (O) 0R2, - (CH2) rC (O) 0R6, - (CH2) rOC (O) R2, - (CH2) rOC (O) R6, - (CH2) rC (O) R2, - (CH2) rC (O) R6, - (CH2) rC (O) N (R 2) (R 2), - (CH 2) r C (O) N (R 2) (R 6), - (CH 2) r N (R 2) -C (O) R 2, - (CH 2) r N (R 2) ) C (O) R 6, - (CH 2) r N (R 6) C (O) R 2, - (CH 2) r N (R 6) C (O) R 6, - (CH 2) r N (R 2) C (O) 0 R 2, - (CH 2) r N (R 2) C (O) 0 R 6, - (CH 2) r N (R 6) C (O) 0 R 2, - (CH 2) r N (R 6) C (O) 0 R 6, - (CH 2) r N (R 2) C (0) N (R 2) (R 6), - (CH 2) r N (R 2) C (O) - N (R 2) (R 2), - (O H 2) r N (R 6) C (O) N (R 2) (R 6) ), - (CH2) rN (R2) SO2R6, - (CH2) rN (R2) -SO2R2, - (CH2) rN (R6) SO2R2, - (CH2) rN (R6) SO2R6, - (CH2) rOC (O ) N (R 2) (R 6), - (CH 2) rOC (O) N (R 2) (R 2), - (CH 2) r SO 2 N (R 2) (R 6), - (CH 2) r SO 2 N (R 2) (R 2) - (CH 2) r SO 2 NHC (O) R 6, - (CH 2) r SO 2 NHC (O) R 2, - (CH 2) r SO 2 NHC (O) 0 R 6, - (CH 2) r SO 2 NHC (O) 0 R 2, - (CH 2) r C (O) NHC (O ) NR2, - (CH2) rC (O) NHC (O) NR6 , - (CH 2) r C (O) NHC (O) R 2, - (CH 2) r C 0 NHC (O) R 6, - (CH 2) r CONHSO 2 R 6, - (CH 2) r CONHSO 2 R 2 - (CH 2) r CONHSO 2 N (R 2) (R 2) (CH2) rC0NHSO2N (R2) (R6), - (CH2) rN (R2) SO2N (R2) (R6), - (CH2) rN (R6) SO2N (R2) (R6), - (CH2) rS (0) ) mR6 and - (CH2) rS (O) mR2; R 3a is hydrogen or C 1-4 alkyl optionally substituted with hydroxy; W is taken from the group: cyano, -C (O) 0R8, -C (O) 0R2l -C (O) 0 (CH2) i-aryl, -C (6) N (R2) (R2), -C (0) ) N (R2) (R8), -C (O) N (R2) (CH2) raryl, -CH2N (R2) - C (O) Re, -CH2N (R2) C (O) (CH2) i-aryl , - (CH2) rOR2, -CH (OH) R2, -CH (OH) - (CH2) i-aryl, -C (O) R2, -C (O) (CH2) i-aryl, 1H-tetrazole- 5-group, 5-amino-1,2,4-oxadiazol-3-yl, S-methyl-1, 4-oxadiazol-S-long, wherein R8 is hydrogen, C1-6alkyl optionally substituted with groups . -OR 2, -C (O) 0 R 2, -CON (R 2) (R 2), -N (R 2) C (O) R 2, -N (R 2) C (O) N (R 2) (R 2), but aryl is phenyl, pyridyl or 1H-tetrazol-5-yl; X is taken from the group: hydrogen, cyano, - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) t-aryl, - (CH2) qN (R2) ) SO 2 (CH 2) t -aryl, - (CH 2 --N (R 2) SO 2 R 2 - (CH 2) q N (R 2) C (O) N (R 2) (CH 2) q -aryl, - (CH 2) q N (R 2) C (O) -N (R 2) (R 2), - (CH 2) q C (O) N (R 2) (R 2), - (CH 2) q C (O) N (R 2) (CH 2) t - CH2) qC (O) 0R2, - (CH2) qC (O) 0 (CH2) raryl, - (CH2) qOR2, - (CH2) qC (O) R2l - (CH2) qC (O) (CH2) raryl, - (CH 2) q CO (O) N (R 2) (CH 2) t -aryl - (CH 2) q O-C (O) N (R 2) (R 2) - (CH 2) q C (O) R 2 - (CH 2) qC (O) (CH2) t -Al, < 2) ^ 2) -C 0) R 2, - (CH 2) q N (R 2) SO 2 N (R 2) (R 2), - (CH 2) q S (O) r r , R 2 and - (CH 2) q S (O) m (CH 2) r aryl, wherein R 2, (CH 2) q and (CH 2) t are optionally substituted with 1 to 2 c 1-4 ', 19', P a / J 'hydroxyl, CMalkoxy, carboxyl, -CONH2, -S (O) moM3, -C (O) 0-C 1-4 alkyl, 1H-tetrazol-5-yl, and aryl is phenyl-naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl optionally substituted with 1 to 3 halogens, 1-3 groups -OR2, -C (O) N (R2) (R2), -C (O) 0R2, 1-3C1-4alkyl, -S (0) ) mR2 or 1H-tetrazol-5-yl; γ taken from the series: hydrogen, C 1-10 alkyl, - (Chhj-aryl, - (C 1 -C 3 C 7 -C 7 cycloalkyl, - (CH 2) q K-C 1-6 alkyl, - (CH 2) q K - (CH 2) t -aryl, - (CH2) qK- (CH2) t-C3-7cycloalkyl containing cycloalkyl -O-, > NR2 or -S-, - (CH2) qK- (CH2) t-C3-7Cycloalkyl, where K is -O -, -S (O) m-, -C (O) NR2-, -CH = CH-, -CsC-, -N (R2) C (O) -, -C (O) NR2-, -C (O) 0- or -OC (O) -, but alkyl, R2, (CH2) q and (CH2) t are optionally substituted with C1-4 alkyl, hydroxy, C1-4alkoxy, carboxyl, -C (O) NH2 or - C (O) O-C 1-6 alkyl, wherein aryl is phenyl, naphthyl, pyridinyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl, or isothiazolyl optionally substituted with 1-3 halogens, 1-3 -OR2 groups, -C (O) 0R2, -C (O) N (R2) (R2), nitro, cyano, benzyl, 1-3Ci * alkyl groups, -S (O) mR2 va 1 H-tetrazol-5-yl; R4 and R5 independently of one another are hydrogen, C1-C6alkyl, optionally substituted with 1 to 5 halogens, 1-3 hydroxyl groups, 1-3C-alkylalkanol, 1-3C1-6alkoxy, phenyl, phenoxy, 2 -furyl, C 1-6 alkoxycarbonyl, -SiOJm-C 1-6 alkyl, or R 4 and R 5 together may form a group - (CH 2) d L - (CH 2) e - wherein La is -C (R 2) 2 -, - O-, -S (O) m- or -N (R 2) -, but d and e are independently 1 to 3, and R 2 has the same meanings; Air: or - (CH2) x-C- (CH2) jT ^ 7a 97 —Z- (CH2) x-C- (CH2) r7-7a wherein x and y are independently 0,1,2 or 3; Z is -N (R 6a) - or -O-, wherein R 6a is hydrogen or C 1-6 alkyl; R6 is hydrogen, C1-6alkyl, or - (CH2) v-aryl, where alkyl and (CH2) v are optionally substituted with 1-2-O (R2), -S (O) mR2, 1H-tetrazol-5 -yl, -C (O) 0R2, -C (O) N (R2) (R2), -SO2N (R2) (R2) or -N (R2) C (O) N (R2) (R2) at aryl is phenyl, pyridinyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolon-1-yl, benzimidazol-2-yl, triazolinonyl optionally substituted with C1-6alkyl, C3-6cycloalkyl, an amino group or a hydroxyl group; R / and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-4 alkyl optionally substituted with: imidazolyl, 6U1 11525 phenyl, indolyl, p-hydroxyphenyl, -OR2, -S (O) mR2 -C ( 0) 0-C 1-6 alkyl, C 3-7 Cycloalkyl, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 7 and R 7a are independently attached to one or both groups R4 and R5, forming alkylene bridges between the terminal nitrogen atom and the R7 and R7a alkyl moieties, wherein the bridge may contain from 1 to 5 carbon atoms, or R7 and R7a may be joined together to form a C3-7cycloalkyl group. I is 0.1 or 2; m is 0.1 or 2; n is 1, 2 or 3; q is 0, 1, 2, 3 or 4; rirO, 1, 2 or 3; t is 0, 1, 2 or 3; over 0.1 or 2; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 3. Savienojums pēc 2. punkta, kurā: R1 ir ņemts no rindas: C-Moalkilgrupa, aril-Ci^alkilgrupa, C3^cikloalkil-CMalkilgrupa, CMalkil-K-C^alkilgrupa, aril-Co-2alkil-K-Ci.2alkilgrupa, C3-7 cikloalkil-Co-2alkil-K-Ci.2alkilgrupa, kur K ir -O-, -S(0)m-, -OC(O)- vai -C(0)0-, alkilgrupas neobligāti aizvietotas ar 1 - 7 halogēna atomiem, -S(0)mR2, 1 - 3 -OR2 vai -C(0)OR2 grupām, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, piridinilgrupa, benzotienilgrupa vai benzofuranilgrupa, kas neobligāti aizvietota ar 1 - 2 CMalkilgrupām, 1-2 halogēna atomiem, 1-2 -OR2 grupām vai metilēndioksigrupām, -S(0)mR2 grupu vai -C(0)OR2 grupu; R2 ņemts no rindas: ūdeņraža atoms, Ci^alkilgrupa, C3.7cikloalkilgrupa, pie tam, ja pie viena atoma pievienotas divas Ci-6alkilgrupas, tās neobligāti savienotas, veidojot C^ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; R3 ņemts no rindas: ūdeņraža atoms vai fenilgrupa, kas neobligāti aizvietota orto stāvoklī ar aizvietotāju no rindas: Ci-ealkilgrupa, -NHSO2CF3, -(CH2)r-(1H-tetrazol-5-ilgrupa), -(CH2)rC(0)OR2, -(CH2)rC(0)N(R2)(R6); R3a ir ūdeņraža atoms vai Ci^alkilgrupa; W ņemts no rindas: ciāngrupa, -C(0)OR2, -C(0)N(R2)(R2). -C(0)N(R2)(CH2)i-fenilgrupa, 1 H-tetrazol-5-ilgrupa vai -(CH2)rOR2', X ņemts no rindas: ūdeņraža atoms, -(CH2)qC(0)N(R2)(R6) vai -(CH2)q-C(0)OR2; Y ņemts no rindas: ūdeņraža atoms. Cvealkilgrupa, -(CH2)t-fenilgrupa, -(CH2)r piridinilgrupa vai -(Chbjt-tiazolilgrupa; 7 R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci^alkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1 - 3 hidroksilgrupām, -S(0)m-Ci.6alkilgrupu vai fenilgrupu; Re ir ūdeņraža atoms vai Ci^alkilgrupa; Air:The compound of claim 2, wherein: R 1 is selected from the group consisting of: C 1 -C 6 alkyl, aryl-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 1-4 alkyl-C 1-4 alkyl, aryl-C 0-2 alkyl-K-C 1-2 alkyl, C3-7 cycloalkyl-Co-2-alkyl-K-C1-2alkyl, where K is -O-, -S (O) m-, -OC (O) - or -C (O) 0-, alkyl optionally substituted with 1 - 7 halogen atoms, -S (O) mR2, 1-3 -OR2 or -C (O) OR2, and aryl taken from phenyl, naphthyl, indolyl, pyridinyl, benzothienyl or benzofuranyl optionally substituted with 1 - 2 CMalkyl groups, 1-2 halogen atoms, 1-2 -OR 2 groups or methylenedioxy groups, -S (O) mR 2 group or -C (O) OR 2 group; R2 is selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, where two C1-6alkyl atoms are attached to one atom, they are optionally bonded to form a C 1-8 ring optionally containing an oxygen or sulfur atom or a group >NR3a; R3 is taken from the group consisting of: hydrogen or phenyl optionally substituted in the ortho position by a substituent from the group: C1-6alkyl, -NHSO2CF3, - (CH2) r- (1H-tetrazol-5-yl), - (CH2) rC (0) ) OR2, - (CH2) rC (O) N (R2) (R6); R 3a is hydrogen or C 1-4 alkyl; W is taken from the group: cyano, -C (O) OR 2, -C (O) N (R 2) (R 2). -C (O) N (R2) (CH2) i-phenyl, 1H-tetrazol-5-yl or - (CH2) rOR2 ', X taken from the hydrogen: - (CH2) qC (O) N ( R2) (R6) or - (CH2) qC (O) OR2; Y taken from the row: hydrogen. C 1-4 alkyl, - (CH 2) t -phenyl, - (CH 2) r pyridinyl or - (Chbjt-thiazolyl; 7 R 4 and R 5 independently of one another are hydrogen, C 1-6 alkyl optionally substituted with 1 to 5 halogens, 1 - 3 hydroxyl groups, -S (O) m -C 1-6 alkyl or phenyl, R e is hydrogen or C 1-6 alkyl; kur x ir 0 vai 1; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, Ci-ealkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2, -S(0)mR2, -C(0)0-Cļ^alkilgrupu, C5.7Cikloalkilgrupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arī R7 un R7a neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5, veidojot alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, veidojot 5 vai 6 locekļu ciklus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot Cacikloalkilgrupu; I ir 0 vai 1; m ir 0, 1 vai 2; n ir 2; q ir 0 vai 1; r ir 0, 1,2 vai 3; t ir 0 vai 1; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuālie diastereomēri.wherein x is 0 or 1; R7 and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-6alkyl optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S (O) mR2, -C (O) 0 -C1-6alkyl, C5-7Cycloalkyl, -N (R2) (R2), -C (O) N (R2) (R2), or R7 and R7a are independently attached to one or both R4 and R5 groups. forming alkylene bridges between the terminal nitrogen atom and the R7 and R7a alkyl moieties to form 5 or 6 membered rings, or R7 and R7a may be joined together to form a Cacycloalkyl group; I is 0 or 1; m is 0, 1 or 2; n and 2; q is 0 or 1; r is 0, 1, 2 or 3; t is 0 or 1; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 4. Savienojums pēc 2. punkta ar formulu (Aib) R1—ļ-N-C-A-N C=0A compound according to claim 2 having the formula (Aib) R 1 - N-C-A-N C = O kurā: Rļ ir ņemts no rindas: Ci-ioalkilgrupa, aril-Ci.3alkilgrupa, aril-C0-ialkil-K-Ci. 2alkilgrupa, kur K ir -O- vai -S(0)m-, bet arilgrupa ņemta no rindas: fenilgrupa, 8 LV 11525 naftilgrupa, indolilgrupa, piridinilgrupa, kas neobligāti aizvietota ar 1 - 2 Ci^alkilgrupām, 1-2 halogēna atomiem, 1-2 -OR2 grupām, -S(0)mR2 grupu vai -C(0)0R2 grupu; R2 ņemts no rindas: ūdeņraža atoms, Ci^alkilgrupa vai C3-7cikloalkilgrupa, pie tam, ja pie viena atoma pievienotas divas Ci^alkilgrupas, tās neobligāti savienotas, veidojot Cs^ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; R3 ņemts no rindas: ūdeņraža atoms vai fenilgrupa, kas neobligāti aizvietota orto stāvoklī ar aizvietotāju no rindas: Ci_3alkilgrupa, -(CH2)r-(1H-tetrazol-5-ilgrupa) vai -(CH2)rC(0)0R2; R3a ir ūdeņraža atoms vai Ci^alkilgrupa; W ņemts no rindas: ciāngrupa, -C(0)0R2 vai -C(0)N(R2)(R2); X ir ūdeņraža atoms vai vai -C(0)0R2; Y ņemts no rindas: ūdeņraža atoms, benzilgrupa, pikolilgrupa vai tiazolilmetilgrupa; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci.3alkilgrupa, neobligāti aizvietota ar 1 - 2 hidroksilgrupām; Air: <f7 (CH2)x—C F*7a kur x ir 0 vai 1; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms vai CMalkilgrupa; m ir 0, 1 vai 2; r ir 0, 1 vai 2; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuālie diastereomēri.wherein: R 1 is selected from the group consisting of C 1-10 alkyl, arylC 1-3 alkyl, aryl-C 0 -C 6 alkyl-K-C 1. 2alkyl, where K is -O- or -S (O) m-, but aryl is selected from phenyl, 8 LV 11525 naphthyl, indolyl, pyridinyl optionally substituted with 1 to 2 C 1-6 alkyl, 1-2 halogen atoms , 1-2 -OR2 groups, -S (O) mR2 or -C (O) 0R2; R2 is selected from the group consisting of hydrogen, C1-4alkyl, or C3-7cycloalkyl, where two C1-4alkyl atoms are optionally attached to form a C 1-4 ring optionally comprising an oxygen or sulfur atom or a group >NR3a; R 3 is taken from the group consisting of: hydrogen or phenyl optionally substituted in the ortho position with a substituent from the group consisting of C 1-3 alkyl, - (CH 2) r - (1H-tetrazol-5-yl) or - (CH 2) r C (O) 0 R 2; R 3a is hydrogen or C 1-4 alkyl; W is taken from the group: cyano, -C (O) 0R2 or -C (O) N (R2) (R2); X is hydrogen or -C (O) 0 R 2; Y is selected from the group consisting of hydrogen, benzyl, picolyl, or thiazolylmethyl; R 4 and R 5 are independently hydrogen, C 1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups; Air: < f7 (CH2) x-C F * 7a where x is 0 or 1; R 7 and R 7a are independently hydrogen or C 1-4 alkyl; m is 0, 1 or 2; r is 0, 1 or 2; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 5. Stereospecifiski raksturots savienojums pēc 2. punkta ar formulu: y R 9 R< R,—j—N-C-A-N C=0 Rs (CHiyW Μ-Χ r3 y 9 kurā Ri, R3, R4, R5, A, W, X, Y un n ir ar 2. punktā minētajām nozīmēm. 6. Savienojums pēc 2. punkta, kas ņemts no rindas:5. A stereospecifically characterized compound according to claim 2 having the formula: y R 9 R < R, - j - NCAN C = 0 Rs (CHiyW Μ-Χ r3 y 9 where R 1, R 3, R 4, R 5, A, W, X, Y and n are as defined in point 2. 6. Compound after 2. from a row: 10 LV 11525 IEZ10 EN 11525 EEZ 1111 tā farmaceitiski pieņemamās sālis un individuālie diastereomēri. 7. Savienojums ar formulu (Bl) c=0 r5 Μ-χ r3 y (Bl) kurā: Rļ ņemts no rindas: Ci-ioalkilgrupa, arilgrupa, aril-Ci.6alktlgrupa, C3_7cikloalkil-Ci^alkilgrupa, Ci-salkil-K-Cļ.salkilgrupa, aril-Co-5alkil-K-Ci.5alkilgrupa, C3.7 cikloalkil-Co-5alkil-K-Ci.5alkilgrupa, kur K ir -O-, -S(0)m-, -N(R2)C(0)-, -OC(O)-, -C(0)0-, -CR2=CR2- vai -C=C-, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, azaindolilgrupa, piridinilgrupa, benzotienilgrupa, benzofuranilgrupa, tiazolilgrupa, benzimidazolilgrupa, pie tam R2 un alkilgrupas neobligāti aizvietotas ar 1 - 9 halogēna atomiem, -S(0)mR2a, 1 - 3 -OR2a vai -C(0)0R2a grupām, bet arilgrupa neobligāti aizvietota ar 1 - 3 Ci^alkilgrupām, 1-3 halogēna atomiem, 1-2 -OR2 grupām vai metilēndioksigrupām vai -S(0)mR2 grupām; 1-2 trifluormetilgrupām vai 12 LV 11525 trifluormetoksigrupam vai nitrogrupām vai grupām: -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -S02N(R2)(R2), -N(R2)S02-C6H5, -N(R2)S02R2 vai 1H-tetrazol-5-ilgrupām; R2 ņemts no rindas: ūdeņraža atoms, Ci.6alkilgrupa, C3-7Cikloalkilgrupa, pje tam , ja pie viena atoma pievienotas divas Ci-6alkilgrupas, tās neobligāti savienotas, veidojot C3-8ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a, kur R3a ir ūdeņraža atoms vai Ci-ealkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; R2a ir ūdeņraža atoms vai Ci-ealkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; R3 ņemts no rindas: -(CH2)r-fenilgrupa, -(CH2)rnaftilgrupa, C3-7 cikloalkilgrupa, pie tam fenilgrupa, naftilgrupa un C3.7cikls neobligāti aizvietoti ar 1 - 3 aizvietotājiem no rindas: Ci.6alkilgrupa, halogēna atoms, -OR2, -NHS02CF3l -(CH2)rOR6, -(CH2)rN(R2)(R6), -(CH^Re), -(CH2)rC(0)0R2, -(CH2)rC(0)0R6, -(CH2)r0C(0)R2, -(CH2)rOC(0)R6, -(CH2)rC(0)R2, -(CH2)rC(0)R6, -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rN(R2)-C(0)R2, -(CH2)rN(R2)C(0)R6, -(CH2)rN(R6)C(0)R2, -(CH2)rN(R6)(^0)R6, -(CH2)rN(R2)C(0)0R2, -(CH2)rN(R2)C(0)0R6, -(CH2)rN(R6)C(0)OR2, -(CH2)rN(R6)C(0)0R6, -(CH2)rN(R2)C(0)N(R2)(R6). -(CH2)rN(R2)C(0)- N(R2)(R2), -(CH2)RN(R6)C(0)N(R2)(R6), -(CH2)rN(R2)S02R6, -(CH2)rN(R2)-S02R2, -(CH2)rN(R6)S02R2, -(CH2)rN(R6)S02R6, -(CH2)r0C(0)N(R2)(R6), -(CH2)rOC(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2), -(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(C^rSOzNHCiOJORe, -(CH2)rS02NHC(0)0R2, -(CH2)rC(0)NHC(0)NR2, -(CH2)rC(0)NHC(0)NR6, -(CH2)rC(0)NHC(0)R2> -(CH2)rC0NHC(0)R6, -(CH2)rC0NHS02R6, -(CH2)rC0NHS02R2, -(CH2)rC0NHS02N(R2)(R2), -(CH2)rC0NHS02N(R2)(R6), -(CH2)rN(R2)S02N(R2)(R6), -(CH2)rN(R6)S02N(R2)(R6), -(CH2)rS(0)mR5 un -(CH2)rS(0)mR2; R3a ir ūdeņraža atoms, Ci-6alkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; X ņemts no rindas: ūdeņraža atoms, ciāngrupa, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)rarilgrupa, -(CH2)qN(R2)S02(CH2)rarilgrupa, -(CH2)q-N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)rarilgrupa, -(CH2)qN(R2)- C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -iCH2^C(0^R2)i^2^p^ -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)rarilgrupa, -(CH2)qOR2 -(CH2)qOC(0)R2, -(CH2)q0C(0)(CH2)t-arilgrupa, -(CH2)q0C(0)N(R2)(CH2)t-arilgrupa, -(CH2)qO-C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)rarilgrupa -gH2)qN(R^-C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2). -(CH2)qS(0)mR2 un -(CH2)qS(0 m(CH2)r arilgrupa, kur R2, (CH2)q un (CH2)t neobligāti aizvietoti ar 11 - 2 < hidroksilgrupu, CMalkoksigrupu, karboksilgrupu, -CONH2, -S(0)mUM3, -C(0)0-CMalkilgrupu, 1 H-tetrazol-5-ilgrupu, bet arilgrupa ir fenUgrupa, naftilgrupa, piridilgrupa, tiazolilgrupa vai 1 H-tetrazol-_5-ilgrupa. kurn; neot.liga aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 grupām -OR2, -C(0)N(K2HK2j, -C(0)0R2,1 - 3 Ci-4alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; 13 Υ ņemts no rindas: ūdeņraža atoms, Ci.i0alkilgrupa, -(CH2)rarilgrupa, -(CH2)q-C^cikloalkilgrupa, -(CH2)q-K-Ci^alkilgrupa, -(CH2)q-K-(CH2)rarilgrupa, -(CH2)q-K-(CH2)t-C3-7cikloalkilgrupa, kas cikloalkilgrupā satur -O-, >NR2 vai -S- -(CH2)q-K-(CH2)t-C3-7cikloalkilgrupa, kur K ir -O-, -S(0)m-, -C(0)NR2-, -CH=CH-, -CsC-, -N(R2)C(0)-, -C(0)NR2-, -C(0)0- vai -OC(O)-, bet alkilgrupas, R2, (CH2)q un (CH2)t neobligāti aizvietotas ar C^alkilgrupu, hidroksilgrupu, CMalkoksigrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci^alkilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, tiazolilgrupa, imidazolilgrupa, indolilgrupa, pirimidinilgrupa, tiadiazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa, tiofenilgrupa, hinolinilgrupa, pirazinilgrupa vai izotiazolilgrupa, kas neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 -OR2 grupām, 1 - 2 grupām -N(R2)(R2), -C(0)0R2, -C(0)N(R2)(R2), nitrogrupām, ciāngrupām, benzilgrupām, 1 - 3 Ci-4alkilgrupām, grupām -S(0)mR2 vai 1H-tetrazol-5-ilgrupām; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci-ealkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1 - 3 hidroksilgrupām, 1 - 3 Ci.i0alkan-oiloksigrupām, 1 - 3 Ci^alkoksigrupām, fenilgrupu, fenoksigrupu, 2-furilgrupu, Ci-6alkoksikarbonilgrupu, -S(0)m-Ci^alkilgrupu, vai arī R4 un R5 abi kopā var veidot grupu -(CH2)d-La-(CH2)e-, kurā La ir -C(R2)2-, -O-, -S(0)m- vai -N(R2)-, bet d un e neatkarīgi viens no otra ir 1 - 3, un R2 nozīmes ir jau minētās; Air: (CH2)x—C—(CH2)“ R7a vai -2-(CH2)x-C-(CH2)y- R7a kur x un y neatkarīgi viens no otra ir 0,1, 2 vai 3; Z ir -N(R6a)- vai -0-, kur R6a ir ūdeņraža atoms vai Ci-ealkilgrupa; R6 ir ūdeņraža atoms, Ci^alkilgrupa vai -(CH2)v-arilgrupa, kur alkilgrupas un (CH2)v grupas neobligāti aizvietotās ar 1 - 2 -0(R2), -S(0)mR2, 1 H-tetrazol-5-ilgrupu, -C(0)0R2l -C(0)N(R2)(R2), -S02N(R2)(R2) vai -N(R2)C(0)N(R2)(R2), pie tam arilgrupa ir fenilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, triazolilgrupa, imidazolilgrupa, tiazolilgrupa, pirazolilgrupa, tiadiazolilgrupa, imidazolon-1-ilgrupa, benzimidazol-2-ilgrupa, triazolinonilgrupa, kas neobligāti aizvietotas ar C^alkilgrupu, C3.6 cikloalkilgrupu, aminogrupu vai hidroksilgrupu; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, Ci-ealkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2, -S(0)mR2, -C(0)0-R2, C3-7cikloalkilgrupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arī R7 un R7a neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5, veidojot 14 LV 11525 alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, pie tam tiltiņš var saturēt no 1 fidz 5 oglekļa atomus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3-7cikloalkilgrupu, ar tādu noteikumu, ka tad, kad R3 ir neaizvietota fenilgrupa, bet X, Y, R4 un R5 ir ūdeņraža atoms, R7 un R7a nav neaizvietota Ci-ealkilgrupa; m ir 0, 1 vai 2; n ir 1, 2 vai 3; q ir 0, 1,2, 3 vai 4; r ir 0, 1,2 vai 3; t ir 0,1,2 vai 3; v ir 0, 1 vai 2; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuāli diastereomēri.its pharmaceutically acceptable salt and individual diastereomers. A compound of formula (B1) c = 0 r5 Μ-χ r 3 y (B1) wherein: R 1 is selected from the group consisting of: C 1-10 alkyl, aryl, arylC 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkyl; -C 1-6 alkyl, aryl-Co-5-alkyl-K-C 1-5 alkyl, C 3-7 cycloalkyl-Co-5-alkyl-K-C 1-5 alkyl, wherein K is -O-, -S (O) m -, -N ( R2) C (O) -, -OC (O) -, -C (O) 0-, -CR2 = CR2- or -C = C-, but aryl is selected from phenyl, naphthyl, indolyl, azaindolyl, pyridinyl , benzothienyl, benzofuranyl, thiazolyl, benzimidazolyl, and R2 and alkyl are optionally substituted with 1 to 9 halogen atoms, -S (O) mR2a, 1-3 -OR2a or -C (O) 0R2a, but aryl optionally substituted with 1 - 3 C 1-6 alkyl groups, 1-3 halogen atoms, 1-2 -OR 2 groups or methylenedioxy groups or -S (O) m R 2 groups; 1-2 trifluoromethyl groups or 12 LV 11525 trifluoromethoxy or nitro groups or groups: -N (R 2) C (O) (R 2), -C (O) 0 R 2, -C (O) N (R 2) (R 2), -SO 2 N ( R2) (R2), -N (R2) SO2-C6H5, -N (R2) SO2R2 or 1H-tetrazol-5-yl; R2 is taken from the group consisting of: hydrogen, C1-6alkyl, C3-7Cycloalkyl, where two C1-6 alkyl groups are attached at one atom, they are optionally bonded to form a C3-8 ring optionally including an oxygen or sulfur atom or a group > NR3a wherein R3a is hydrogen or C1-6alkyl optionally substituted by hydroxy; R 2a is hydrogen or C 1-6 alkyl optionally substituted by hydroxy; R 3 is selected from the group consisting of - (CH 2) r -phenyl, - (CH 2) -naphthyl, C 3-7 cycloalkyl, phenyl, naphthyl and C 3-7 optionally substituted with 1 to 3 substituents from C 1-6 alkyl, halogen, -OR 2, -NHSO 2 CF 3 - (CH 2) r R 6, - (CH 2) r N (R 2) (R 6), - (CH 2 R 4), - (CH 2) r C (O) 0 R 2, - (CH 2) r C (O) 0 R 6, - (CH 2) r 0 C (O) R 2, - (CH 2) rOC (O) R 6, - (CH 2) r C (O) R 2, - (CH 2) r C (O) R 6, - (CH 2) r C (O) N ( R2) (R2), - (CH2) rC (O) N (R2) (R6), - (CH2) rN (R2) -C (O) R2, - (CH2) rN (R2) C (O) R6 , - (CH2) rN (R6) C (O) R2, - (CH2) rN (R6) (^ O) R6, - (CH2) rN (R2) C (O) 0R2, - (CH2) rN (R2) ) C (O) 0R6, - (CH2) rN (R6) C (O) OR2, - (CH2) rN (R6) C (O) 0R6, - (CH2) rN (R2) C (O) N (R2) ) (R6). - (CH 2) r N (R 2) C (O) - N (R 2) (R 2) - (CH 2) R N (R 6) C (O) N (R 2) (R 6) - (CH 2) r N (R 2) SO 2 R 6 , - (CH 2) r N (R 2) -SO 2 R 2, - (CH 2) r N (R 6) SO 2 R 2, - (CH 2) r N (R 6) SO 2 R 6, - (CH 2) r C (O) N (R 2) (R 6) - CH2) rOC (O) N (R 2) (R 2), - (CH 2) r SO 2 N (R 2) (R 6), - (CH 2) r SO 2 N (R 2) (R 2), - (CH 2) r SO 2 NHC (O) R 6 - ( CH2) rSO2NHC (O) R2, - (C1-4SO2NHCOORORe, - (CH2) rSO2NHC (O) 0R2, - (CH2) rC (O) NHC (O) NR2, - (CH2) rC (O) NHC (0) NR6, - (CH2) rC (O) NHC (O) R2 > - (CH2) R10NHC (O) R6, - (CH2) rC0NHSO2R6, - (CH2) rC0NHSO2R2, - (CH2) rC0NHSO2N (R2) (R2), - (CH2) rC0NHSO2N (R2) (R6), - (CH2) rN (R2) SO2N (R2) (R6), - (CH2) rN (R6) SO2N (R2) (R6), - (CH2) rS ( 0) mR5 and - (CH2) rS (O) mR2; R3a is hydrogen, C1-6alkyl optionally substituted with hydroxyl; X is taken from hydrogen, cyano, - (CH2) qN (R2) C (0); ) R2, - (CH2) qN (R2) C (O) (CH2) raryl, - (CH2) qN (R2) SO2 (CH2) raryl, - (CH2) qN (R2) SO2R2, - (CH2) qN ( R2) C (O) N (R2) (CH2) raryl, - (CH2) qN (R2) - C (O) N (R2) (R2), - (CH2) qC (O) N (R2) (R2) ), -ICH2 ^ C (O2R2) ^ 2 [beta] - (CH2) qC (O) 0R2, - (CH2) qC (O) 0 (CH2) raryl, - (CH2) qOR2 - (CH2) qOC (O) R2, - (CH 2) q0C (O) (CH2) t -aryl, - (CH2) qOC (O) N (R2) (CH2) t -aryl, - (CH2) qO-C (O) N (R2) (R2), - (CH 2) q C (O) R 2, - (CH 2) q C (O) (CH 2) raryl-g H 2) q N (R 1 -C (O) 0 R 2, - (CH 2) q N (R 2) SO 2 N (R 2) (R 2) ). - (CH2) qS (O) mR2 and - (CH2) qS (0m (CH2) r aryl, wherein R2, (CH2) q and (CH2) t are optionally substituted with 11-2 < hydroxyl, CMalkoxy, carboxyl, -CONH2, -S (O) mUM3, -C (O) 0-CMalkyl, 1H-tetrazol-5-yl, and aryl is phenU, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-ylcupn; replaced by 1 to 3 halogens, 1-3 groups -OR2, -C (O) N (K2HK2j, -C (O) 0R2.1-3 Ci-4alkyl, -S (O) mR2 or 1H- tetrazol-5-long; 13 Υ is taken from the group: hydrogen, C 1-10 alkyl, - (CH 2) raryl, - (CH 2) q C 1-4 cycloalkyl, - (CH 2) q K-C 1-6 alkyl, - (CH 2) q K- ( CH2) raryl, - (CH2) qK- (CH2) t-C3-7cycloalkyl, which contains cycloalkyl -O-, > NR2 or -S- (CH2) qK- (CH2) t-C3-7cycloalkyl, where K and -O-, -S (O) m-, -C (O) NR 2 -, -CH = CH-, -C s C-, -N (R 2) C (O) -, -C (O) NR 2 -, -C (O) O- or -OC (O) -, but alkyl, R 2, (CH 2) q and (CH 2) t are optionally substituted with C 1-4 alkyl, hydroxy, C 1-4 alkoxy, carboxyl, -C (O) NH 2, or - C (O) O-C 1-6 alkyl, wherein aryl is phenyl, naphthyl, pyridinyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl, or isothiazolyl optionally substituted with 1-3 halogens, 1-3 -OR2 groups, 1-2 groups -N (R2) (R2), -C (O) 0R2, -C (O) N (R2) (R2) ), nitro groups, cyano groups, benzyl groups, 1-3 C 1-4 alkyl groups, -S (O) m R 2 or 1H-tetrazol-5-yl groups; R4 and R5 are independently from each other hydrogen, C1-6alkyl, optionally substituted with 1 to 5 halogens, 1-3 hydroxyl groups, 1-3C 1-10 alkanalkoxy groups, 1-3C1-6 alkoxy groups, phenyl, phenoxy, 2 -furyl, C 1-6 alkoxycarbonyl, -S (O) m -C 1-6 alkyl, or R 4 and R 5 together may form a group - (CH 2) d -L- (CH 2) e - wherein La is -C (R 2) 2-, -O-, -S (O) m- or -N (R 2) -, but d and e are independently 1 to 3, and R 2 has the same meanings; Air: (CH2) x-C (CH2) R7a or -2- (CH2) x-C- (CH2) y-R7a wherein x and y are independently 0,1, 2 or 3; Z is -N (R 6a) - or -O-, wherein R 6a is hydrogen or C 1-6 alkyl; R6 is hydrogen, C1-6alkyl or - (CH2) v-aryl, where alkyl and (CH2) v are optionally substituted with 1-22 (R2), -S (O) mR2, 1H-tetrazol-5 -yl, -C (O) 0R2l -C (O) N (R2) (R2), -SO2N (R2) (R2) or -N (R2) C (O) N (R2) (R2), in addition aryl is phenyl, pyridinyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolon-1-yl, benzimidazol-2-yl, triazolinonyl optionally substituted with C 1-6 alkyl, C 3-6 cycloalkyl , amino or hydroxy; R7 and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-6alkyl optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S (O) mR2, -C (O) 0 -R 2, C 3-7 cycloalkyl, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 7 and R 7a are independently attached to one or both R 4 and R 5 to form 14 EN 11525 alkylene bridges between the extreme nitrogen atom and the R7 and R7a alkyl moieties, wherein the bridge may contain from 1 to 5 carbon atoms, or R7 and R7a may be joined together to form a C3-7cycloalkyl group, provided that then when R 3 is unsubstituted phenyl but X, Y, R 4 and R 5 are hydrogen, R 7 and R 7a are not unsubstituted C 1-6 alkyl; m is 0, 1 or 2; n is 1, 2 or 3; q is 0, 1,2, 3 or 4; r is 0, 1, 2 or 3; t is 0,1,2 or 3; v is 0, 1 or 2; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 8. Savienojums pēc 7. punkta, kurā: R1 ir ņemts no rindas: Ci_ioalkilgrupa, aril-C-Malkilgrupa, C3-6Cikloalkil-Ci^alkilgrupa, Ci-4alkil-K-Ci-2alkilgrupa, aril-Co-2alkil-K-Ci_2alkilgrupa, C3.7 cikloalkil-C0-2alkil-K-Ci-2alkilgrupa, kur K ir -O-, -S(0)m-, -OC(O)- vai -C(0)0-, alkilgrupas neobligāti aizvietotas ar 1 - 7 halogēna atomiem, -S(0)mR2, 1 - 3 -OR2 vai -C(0)OR2 grupām, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, piridinilgrupa, benzotienilgrupa vai benzofuranilgrupa, kas neobligāti aizvietota ar 1 - 2 Ci^alkilgrupām, 1-2 halogēna atomiem, 1 - 2 -OR2 grupām vai metilēndioksigrupām, -S(0)mR2 grupu vai -C(0)OR2 grupu; R2 ņemts no rindas: ūdeņraža atoms, Ci-6alkilgrupa, C3.7cikloalkilgrupa, pie tam, ja pie viena atoma pievienotas divas Ci-6alkilgrupas, tās neobligāti savienotas, veidojot C^ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; R3 ir fenilgrupa, neobligāti aizvietota ar 1 - 2 Ci^alkilgrupām, 1-2 halogēna atomiem, 1 - 2 -OR2 grupām un neobligāti aizvietota orto stāvoklī ar aizvietotāju no rindas: ,Λ1, x -NHS02CF3, -(CH2)rOR8, -(CH2),N(R2)(R8), -(CH2),(R8), -(c,^)'C(0)OR2, -(CH2),C(0)0R6, -(CH2),OC(0)R2, -(CH2),0C(0)R8 -(CH2),C(0)R8, -(CH2),C(0)N(R2)(R2). -(CH2),C(0)N(R2)(R6). -¾¾¾¾1-C(0)R2, -(CH2)rN(R2)C(0)R8, -(CH2)rN(R6)C(0)R2, -(CH2),N(R2)C(0)0R2. -(CH2),N(R2)C(0)0R6, -(CH2),N(R8)C(0)0R8, -(CH2),N(R2)C(0)N(R2)(R8), D(CH!^<R2ļ9(0' N(R2)(R2). -(CH2)RN(R8)C(0)N(R2)(R8). -(cH2),N(R2)S02R^ -(0^),1N(R2)-S02R2, -(CH2),N(R8)S02R2, -(CHdrNļReļSOzRe, M1 -(CH2),0C(0)N(R2)(R2). -(CH2),S02N(R2)(Rs), mhc,o10r ’ - CH2),S02NHC(0)R8. -(CH2),S02NHC(0)R2, ^u^niNHCiSNR8' - CH2),S02NHC(0)0R2. -(CH2),C(0)NHC(0)NR2, - CH2),C(0)NHC(0)R2, -(CH2),C0NHC(0)R8. -(CHi^CONHSOaRa, -(CH2),C0NHS02R2. -(CH2),C0NHS02N(R2)(R2), K -(CH2)rN(R2)S02N(R2)(R8). -(CH2),N(R8)S02N(R2)(R8), -(CH2), ( )m -(CH2)rS(0)mR2, 15 R3a ir ūdeņraža atoms vai C-Malkilgrupa; X ņemts no rindas: ūdeņraža atoms, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)t-arilgrupa, -(CH2)qN(R2)S02(CH2)rarilgrupa, -(CH2)q-N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)rarilgrupa, -(CH2)qN(R2)- C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)rarilgrupa, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)t-arilgrupa, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)rarilgrupa, -(CH2)qN(R2)-C(0)0R2, -(CH2)qS(0)mR2 un -(CH2)qS(0)m(CH2)t-arilgrupa, kur R2 neobligāti aizvietots ar hidroksilgrupu, karboksilgrupu, -CONH2, -S(0)mCH3, -C(0)0-Ci^alkilgrupu, 1 H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa vai 1 H-tetrazol-5-ilgrupa, kuras neobligāti aizvietotas ar 1 - 2 halogēna atomiem, 1 - 2 grupām -OR2, -C(0)NH2, -C(0)0R2, 1 - 3 C^alkilgrupām, -S(0)mR2 vai 1 H-tetrazol-5-ilgrupu; Y ņemts no rindas: ūdeņraža atoms, Ci.salkilgrupa, -(CH2)rarilgrupa, -(CH2)q-Cs-eCikloalkilgrupa, -(CH2)q-K-C1.6alkilgrupa, -(CH2)q-K-(CH2),-arilgrupa, -(CH2)q-K-(CH2)rC3-7cikloalkilgrupā, kas cikloalkilgrupā satur -O-, >NR2 vai -S-, -(CH2)q-K-(CH2)rC5.6Cikloalkilgrupa, kur K ir -0- vai -S(0)m-, bet alkilgrupas neobligāti aizvietotas ar hidroksilgrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci-4alkilgrupu vai 1 H-tetrazol-5-ilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, tiazolilgrupa, imidazolilgrupa, pirimidinilgrupa, tiadiazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa vai tiofenilgrupa, kas neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 -0R2 grupām, 1 - 2 -N(R2)(R2) grupām, -C(0)0R2, -C(0)N(R2)(R2), ciāngrupu, 1 - 2 Ci^alkilgrupām, benzilgrupu, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; R4 un Rs neatkarīgi viens no otra ir ūdeņraža atoms, Ci-6alkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1 - 3 hidroksilgrupām, -S(0)m-Ci_6alkilgrupu vai fenilgrupu; R6 ir ūdeņraža atoms, C^alkilgrupa vai -(CH2)v-arilgrupa, kur alkilgrupas un (CH2)V grupas neobligāti aizvietotas ar 1 - 2 -0(R2), -S(0)mR2, -C(0)0R2, -C(0)N(R2)(R2), -S02N(R2)(R2) vai -N(R2)C(0)N(R2)(R2), pie tam arilgrupa ir fenilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, triazolilgrupa, imidazolilgrupa, tiazolilgrupa, pirazolilgrupa, tiadiazolilgrupa, benzimidazol-2-ilgrupa, kas neobligāti aizvietotas ar Ci.6alkilgrupu, C3.6 cikloalkilgrupu, aminogrupu vai hidroksilgrupu: Air: F? (CH2)x-C- ^7a kur x ir 0 vai 1; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, Cļ-ealkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, 16 LV 11525 fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2> -S(0)mR2, -C(0)0R2, C5.7cikloalkilgrupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arī R7 un R7a neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5, veidojot alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, pie tam tiltiņš var saturēt no 1 līdz 5 oglekļa atomus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3cikloalkilgrupu, ar tādu noteikumu, ka tad, kad R3 ir neaizvietota fenilgrupa, bet X, Y, R4 un R5 ir ūdeņraža atoms, R7 un R7a nav neaizvietota C^ealkilgrupa; m ir 0, 1 vai 2; n ir 2; q ir 0, 1,2 vai 3; r ir 0, 1, 2 vai 3; t ir 0, 1,2 vai 3; v ir 0, 1 vai 2; kā arī šī savienojuma farmaceitiski pieņemamās salis un individuāli diastereomēri.A compound according to claim 7, wherein: R 1 is selected from the group consisting of C 1-10 alkyl, aryl-C-alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-4 alkyl-K-C 1-2 alkyl, aryl-Co-2-alkyl-K- C1-2alkyl, C3-7cycloalkyl-C0-2alkyl-K-C1-2alkyl, where K is -O-, -S (O) m-, -OC (O) - or -C (O) 0-, alkyl optionally substituted with 1-7 halogen atoms, -S (O) mR2, 1-3 -OR2 or -C (O) OR2, but aryl is taken from phenyl, naphthyl, indolyl, pyridinyl, benzothienyl or benzofuranyl optionally substituted with 1 to 2 C 1-6 alkyl groups, 1 to 2 halogen atoms, 1 to 2 -OR 2 groups or methylenedioxy groups, -S (O) m R 2 or -C (O) OR 2; R2 is selected from the group consisting of: hydrogen, C1-6alkyl, C3-7cycloalkyl, where two C1-6 alkyl groups are attached to one atom, they are optionally bonded to form a C1- ring optionally including an oxygen or sulfur atom or a group >NR3a; R 3 is phenyl optionally substituted with 1 to 2 C 1-6 alkyl, 1 to 2 halogen atoms, 1 to 2 -OR 2 groups, and optionally substituted in the ortho to the substituent:, Λ 1, x -NHSO 2 CF 3, - (CH 2) r R 8, - (CH2), N (R2) (R8), - (CH2), (R8), - (c, ^) 'C (O) OR2, - (CH2), C (O) 0R6, - (CH2), OC (O) R2, - (CH2), 0C (O) R8 - (CH2), C (O) R8, - (CH2), C (O) N (R2) (R2). - (CH 2), C (O) N (R 2) (R 6). -¾¾¾¾1-C (0) R2, - (CH2) rN (R2) C (O) R8, - (CH2) rN (R6) C (O) R2, - (CH2), N (R2) C (O) 0R2. - (CH 2), N (R 2) C (O) 0 R 6, - (CH 2), N (R 8) C (O) 0 R 8, - (CH 2), N (R 2) C (O) N (R 2) (R 8) , D (CH 2 OH < R 2 R 9 (O 'N (R 2) (R 2). - (CH 2) R N (R 8) C (O) N (R 2) (R 8) - (cH 2), N (R 2) SO 2 R - (O), 1N (R 2) -SO 2 R 2, - (CH 2), N (R 8) SO 2 R 2, - (CH 3 R 4 R 8 SO 2 R 10, M 1 - (CH 2), O C (O) N (R 2) (R 2) - (CH 2) ), SO 2 N (R 2) (R 5), mhc, o 10 r '- CH 2), SO 2 NHC (O) R 8 - (CH 2), SO 2 NHC (O) R 2, R 4NHCiSNR 8' - CH 2), SO 2 NHC (O) 0 R 2. - (CH2), C (O) NHC (O) NR2, --CH2), C (O) NHC (O) R2, - (CH2), C0NHC (O) R8. - (CH 2 - CONHSO 2 R a, - (CH 2), C 0 NHSO 2 R 2 - (CH 2), C 0 N HSO 2 N (R 2) (R 2), K - (CH 2) r N (R 2) SO 2 N (R 2) (R 8) - (CH 2), N ( R8) SO2N (R2) (R8), - (CH2), () m - (CH2) rS (O) mR2, 15a R3a is hydrogen or C-alkyl; X is taken from hydrogen: - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) t -Aryl, - (CH2) qN (R2) SO2 (CH2) raryl, - (CH2) qN (R2) ) SO2R2, - (CH2) qN (R2) C (O) N (R2) (CH2) raryl, - (CH2) qN (R2) - C (O) N (R2) (R2) - (CH2) qC (0) N (R 2) (R 2), - (CH 2) q C (O) N (R 2) (CH 2) raryl, - (CH 2) q C (O) 0 R 2, - (CH 2) q C (O) 0 (CH 2) t-aryl, - (CH 2) q CO (O) R 2, - (CH 2) q CO (O) (CH 2) raryl, - (CH 2) q N (R 2) -C (O) 0 R 2, - (CH 2) q S (0) mR2 and - (CH2) qS (O) m (CH2) t -aryl, wherein R2 is optionally substituted with hydroxy, carboxyl, -CONH2, -S (O) mCH3, -C (O) 0-C1-4alkyl, 1H -tetrazol-5-yl, but aryl is phenyl, naphthyl, pyridinyl or 1H-tetrazol-5-yl optionally substituted with 1 to 2 halogens, 1 to 2 -OR2, -C (O) NH2, - C (O) 0R2, 1-3C1alkyl, -S (O) mR2 or 1H-tetrazol-5-yl; Y is taken from the group: hydrogen, C1-6alkyl, - (CH2) raryl, - (CH2) q-C8-Cycloalkyl, - (CH2) qK-C1-6alkyl, - (CH2) qK- (CH2) -, aryl , - (CH2) qK- (CH2) rC3-7cycloalkyl containing cycloalkyl -O-, > NR2 or -S-, - (CH2) qK- (CH2) rC5.6Cycloalkyl wherein K is -O- or - S (O) m-, but alkyl optionally substituted with hydroxy, carboxyl, -C (O) NH 2 or -C (O) O-C 1-4 alkyl or 1 H-tetrazol-5-yl, wherein aryl is phenyl, naphthyl , pyridinyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl optionally substituted with 1 to 3 halogens, 1-3 -R2 groups, 1-2-N ( R2) for (R2) groups, -C (O) 0R2, -C (O) N (R2) (R2), cyano, 1-2C1-6alkyl, benzyl, -S (O) mR2 or 1H-tetrazol-5 -yl; R4 and R5 independently of one another are hydrogen, C1-6alkyl, optionally substituted with 1-5 halogens, 1-3 hydroxyl groups, -S (O) m-C1-6alkyl or phenyl; R6 is hydrogen, C1-4 alkyl, or - (CH2) v-aryl, where the alkyl and (CH2) V groups are optionally substituted with 1-22 (R2), -S (O) mR2, -C (O) 0R2 , -C (O) N (R 2) (R 2), -SO 2 N (R 2) (R 2) or -N (R 2) C (O) N (R 2) (R 2), wherein aryl is phenyl, pyridinyl, 1H- tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl optionally substituted with C 1-6 alkyl, C 3-6 cycloalkyl, amino or hydroxy: Air: F? (CH 2) x-C 1-7a wherein x is 0 or 1; R7 and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-6alkyl, optionally substituted with: imidazolyl, 16L-11525 phenyl, indolyl, p-hydroxyphenyl, -OR2 > -S (O) mR2, -C (O) 0R2, C5-7cycloalkyl, -N (R2) (R2), -C (O) N (R2) (R2), or R7 and R7a independently of one another linked to one or both of R4 and R5 to form alkylene bridges between the terminal nitrogen atom and the R7 and R7a alkyl moieties, wherein the bridge may contain from 1 to 5 carbon atoms, or R7 and R7a may be joined together to form a C3-cycloalkyl group, with the proviso that when R 3 is unsubstituted phenyl, but X, Y, R 4 and R 5 are hydrogen, R 7 and R 7a are not unsubstituted C 1-4 alkyl; m is 0, 1 or 2; n and 2; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; t is 0, 1, 2 or 3; v is 0, 1 or 2; as well as pharmaceutically acceptable fractions and individual diastereomers of this compound. 9. Savienojums pēc 7. punkta ar formulu (Blb): Η. H I I9. A compound according to claim 7 having the formula (B1b): Η. H I I R3 (Blb) kurā: Rļ ir ņemts no rindas: Ci.ioalkilgrupa, aril-Ci-3alkilgrupa, C3-7cikloalkil-Ci-3alkilgrupa, aril-Co-ialkil-K-Ci.2alkilgrupa, kur K ir -O- vai -S(0)m-, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, piridinilgrupa, indolilgrupa, azaindolilgrupa vai benzimidazolilgrupa, kas neobligāti aizvietota ar 1 - 2 Ci-4alkilgrupām, 1 - 2 halogēna atomiem, 1-2 -OR2 grupām, -S(0)mR2 grupu vai -C(0)0R2 grupu; R2 ņemts no rindas: ūdeņraža atoms, Ci^alkilgrupa, C3.7cikloalkilgrupa, pie tam, ja pie viena atoma pievienotas divas Ci^alkilgrupas, tās neobligāti savienotas, veidojot C5.7ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3aI R3 ir fenilgrupa, neobligāti aizvietota ar 1 - 2 Ci^alkilgrupām, 1-2 halogēna atomiem vai 1-2 -OR2 grupām un neobligāti aizvietota orto stāvoklī ar aizvietotāju no rindas:R3 (B1b) wherein: R1 is selected from the group consisting of C1-10alkyl, aryl-C1-3alkyl, C3-7cycloalkyl-C1-3alkyl, aryl-Co-alkylalkyl-K-C1-2alkyl, wherein K is -O- or - S (O) m- but aryl taken from the group phenyl, naphthyl, indolyl, pyridinyl, indolyl, azaindolyl or benzimidazolyl optionally substituted with 1 to 2 C 1-4 alkyl groups, 1 to 2 halogens, 1-2 to -OR 2 groups , -S (O) mR2 or -C (O) 0R2; R2 is selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, and when two C1-4alkyl atoms are attached to one atom, they are optionally bonded to form a C5.7 ring optionally containing an oxygen or sulfur atom or a group > NR3aI R3 is phenyl optionally substituted with 1 to 2 C1-4alkyl, 1-2 halogen atoms or 1-2 -OR2 groups and optionally substituted in the ortho position by the substituent: 17 :K«KK: .SSS»».' sasssr «sssk1 ««« .(CH2),S02NHC(0)0R2, -(CH2),C0NHC(0)R6, -(CH2),C0NHS02R2i -(CH2)rS(0)mR6 un -(CH2)rS(0)mR2; R3a ir ūdeņraža atoms vai Ci^alkilgrupa; X ņemts no rindas: ūdeņraža atoms, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)rarilgrupa, -(CH2)qN(R2)S02(CH2)rarilgrupa ^CH^-N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)t-arilgrupa, -(CH2)qN(R2)C(0)-N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2) CH2 t-arilgrupa, -(CH2)qC(0)0R2l -(CH2)qC(0)0(CH2)t-arilgrupa, '(^)qOC(0)R2, -(CH2)q0C(0)(CH2)t-arilgrupa, -(CH2)qN(R2)-C(0)0R2, -(CH2)qS(0)mR2 un -(CH2)qS(0)m(CH2)t-arilgrupa, kur R2 neobligāti aizvietots ar hidroksilgrupu. karboksilgrupu, -CONH2, -S(0)mCH3, -C(0)0-Ci^alkilgrupu vai 1 H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa, naftilgrupa vai piridinilgrupa, kuras neobligāti aizvietotas ar 1 - 2 halogēna atomiem, 1-2 grupām -OR2, -C(0)0R2,1 - 3 C^alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; Y ņemts no rindas: ūdeņraža atoms, Ci-ealkilgrupa, -(CH2)t-arilgrupa, -(CH2)q-Cs^cikloalkilgrupa, -(CH2)q-K-Ci-6alkilgrupa, -(CH2)q-K-(CH2)t-arilgrupa, -(CH2)q-K-(CH2)rC5.6cikloalkilgrupa, kur K ir -S(0)m-, bet alkilgrupas neobligāti aizvietotas ar hidroksilgrupu, karboksilgrupu, -C{0)NH2 vai -C(0)0-Ci-4alkilgrupu vai 1H-tetrazol-5-ilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, tiazolilgrupa, imidazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa vai tiofenilgrupa, kas neobligāti aizvietotas ar 1-2 halogēna atomiem, 1 - 2 -OR2 grupām, 1 - 2 -N(R2)(R2) grupām, -C(0)0R2, 1 - 2 CMalkilgrupām, -S(0)mR2 vai 1 H-tetrazol-5-ilgrupu; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci^alkilgrupa vai Ci-3alkilgrupa, kas neobligāti aizvietota ar 1 - 2 hidroksilgrupām; R6 ir ūdeņraža atoms, Cļ-ealkilgrupa vai -(CH2)v-arilgrupa, kur alkilgrupas un (CH2)v grupas neobligāti aizvietotas ar 1 - 2 -0(R2), -S(0)mR2, -C(0)0R2, -C(0)N(R2)(R2), -S02N(R2)(R2) vai -N(R2)C(0)N(R2)(R2), pie tam arilgrupa ir fenilgrupa, piridinilgrupa, 1 H-tetrazol-5-ilgrupa, triazolilgrupa, imidazolilgrupa, tiazolilgrupa, pirazolilgrupa, tiadiazolilgrupa, benzimidazol-2-ilgrupa, kas neobligāti aizvietotas ar C^alkilgrupu, C3-6 cikloalkilgrupu, aminogrupu vai hidroksilgrupu; A ir: lļ*7 (CH2)x—C — ^7a 18 LV 11525 kur x ir 0 vai 1; R7 un F*7a neatkarīgi viens no otra ir ūdeņraža atoms, fenilgrupa, Ci^alkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2 vai -S(0)mR2, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3cikloalkilgrupu, ar tādu noteikumu, ka tad, kad R3 ir neaizvietota fenilgrupa, bet X, Y, R4 un R5 ir ūdeņraža atoms, R7 un R7a nav neaizvietota Ci^alkilgrupa; m ir 0, 1 vai 2; q ir 0, 1,2 vai 3; rirO, 1,2 vai 3; tirO, 1, 2 vai 3; v ir 0, 1 vai 2; kā arī šī savienojuma farmaceitiski pieņemamās sālīs un individuāli diastereomēri.17: K «KK: .SSS» ». ' (CH2), SO2NHC (O) 0R2, - (CH2), C0NHC (O) R6, - (CH2), C0NHSO2R2i - (CH2) rS (O) mR6 and - (CH2) rS ( 0) mR2; R 3a is hydrogen or C 1-4 alkyl; X taken from the series: hydrogen, - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) raryl, - (CH2) qN (R2) S02 (CH2) ) Raryl-CH2 -N (R2) SO2R2, - (CH2) qN (R2) C (O) N (R2) (CH2) t -aryl, - (CH2) qN (R2) C (O) -N ( R2) (R2), - (CH2) qC (O) N (R2) (R2), - (CH2) qC (O) N (R2) CH2 t-aryl, - (CH2) qC (O) 0R2l - ( CH 2) q C (O) 0 (CH 2) t -aryl, '(^) qOC (O) R 2, - (CH 2) q CO (O) (CH 2) t -aryl, - (CH 2) q N (R 2) -C ( 0) 0R2, - (CH2) qS (O) mR2 and - (CH2) qS (O) m (CH2) t-aryl, wherein R2 is optionally substituted by hydroxy. carboxyl, -CONH2, -S (O) mCH3, -C (O) 0-C1-4 alkyl or 1H-tetrazol-5-yl, but aryl is phenyl, naphthyl or pyridinyl optionally substituted with 1 to 2 halogens , 1-2 for -OR2, -C (O) 0R2.1-3C1alkyl, -S (O) mR2 or 1H-tetrazol-5-yl; Y is taken from the group: hydrogen, C1-6alkyl, - (CH2) t-aryl, - (CH2) q-C5-6cycloalkyl, - (CH2) qK-C1-6 alkyl, - (CH2) qK- (CH2) t -aryl, - (CH2) qK- (CH2) rC5.6cycloalkyl, where K is -S (O) m-, but alkyl is optionally substituted with hydroxy, carboxyl, -C (O) NH2 or -C (O) 0- C1-4alkyl or 1H-tetrazol-5-yl, wherein aryl is phenyl, naphthyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl optionally substituted with 1-2 halogens, 1 to 2 -OR2 groups , 1-2 -N (R2) (R2), -C (O) 0R2, 1-2Calkyl, -S (O) mR2 or 1H-tetrazol-5-yl; R4 and R5 are independently from each other hydrogen, C1-6alkyl or C1-3alkyl optionally substituted with 1 to 2 hydroxyl groups; R6 is hydrogen, C1-6alkyl, or - (CH2) v-aryl, where alkyl and (CH2) v are optionally substituted with 1-22 (R2), -S (O) mR2, -C (O) 0R2 , -C (O) N (R 2) (R 2), -SO 2 N (R 2) (R 2) or -N (R 2) C (O) N (R 2) (R 2), wherein aryl is phenyl, pyridinyl, 1 H -tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl optionally substituted with C 1-6 alkyl, C 3-6 cycloalkyl, amino or hydroxy; A is: ll * 7 (CH2) x - C - ^ 7a 18 LV 11525 where x is 0 or 1; R7 and F * 7a independently of one another are hydrogen, phenyl, C1-6 alkyl optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2 or -S (O) mR2, or R7 and R7a can be be linked to each other to form a C3-cycloalkyl group, provided that when R3 is unsubstituted phenyl, X, Y, R4 and R5 are hydrogen, R7 and R7a are not unsubstituted C1-6 alkyl; m is 0, 1 or 2; q is 0, 1, 2 or 3; rirO, 1,2 or 3; tirO, 1, 2 or 3; v is 0, 1 or 2; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 10. Savienojums pēc 7. punkta ar formulu (Bic): R1—ON-C-A-NA compound according to claim 7 having the formula (Bic): R1-ON-C-A-N 1 Η H - I I II1 Η H - I I II c=o o kurā: R1 ir ņemts no rindas:c = o o where: R 1 is taken from the row: H H -N"CHrH H -N " CHr HH H 19H 19 vai to pozicionālie izomēri, ja tie nav specifiski norādīti formulās; _ tc no rindas- ūdeņraža atoms, C^alkilgrupa, C^cikloalkilgrupa pie R2 ņemts no nndas^eņ tevjeļļotas ^ c^a|kNgrupas, tas_ neobligāti savienotas, veidojot C5.7ciklu, kas neobligāti ietver skābekja vai sera atomu, vai grupu >NR3aI d v fcniir-imna neobliaāti aizvietota orto stāvoklī ar aizvietotāju no rindas: NHsS CfT (CH°)X -(CH2),N(R2)(R6), -(CH2),(Re), -(CH^OļOR,, ORe^),00(0)^, -(CH2)r0C(0)R6, -(CH2),C(0)R2, iCH2)C(0)R6 -(CH2)rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6). -(CH2)rN(R2)- R2^ -(C H 2) rN( R2) C (O) R6. -(CH2)rN(R6)C(0)R2, -(CH2)rN(R2)C(0)OR2, -(CH2)rN(R2)C(0)0R6. -(CH2)rN(R6)C(0)0R2l -(CH2):N(S)C(0)0R:: -(CH2)rN(R2)C(0)N(R2)(Re), ^0 - N(R2)(R2). -(CH2)rN(R6)C(0)N(R2)(R6), -(CH2)rN(R2)S02R6, ^;^^)rN(R2)-S02R2, -(CH2)rN(R6)S02R2, -(CH2),N(R6)S02R6, -(CH2)rOC(0)N(R2)(R6), -(CH2)r0C(0)N(R2)(R2), -(CH2)rS02N(R2)(R6), -(CH2)rS02N(R2)(R2), -(CH2)rS02NHC(0)R6, -(CH2)rS02NHC(0)R2, -(CH2)rS02NHC(0)0R6, -(CH2)rS02NHC(0)0R2, -(CH2)rCONHS02R6, -(CH2)rC0NHS02R2> -(CH2)rS(0)mR6 un-(CH2)rS(0)mR2; R3a ir ūdeņraža atoms vai Ci^alkilgrupa; X ņemts no rindas: ūdeņraža atoms, grupas 20 LV 11525or their positional isomers, unless specifically specified in the formulas; cc-cycloalkyl at R2 taken from N-thiol-hydrogenated, c 1-4 -cycloalkyl, it is optionally bonded to form C5.7, optionally including oxygen or sera, or group >; NR3aI dv-imnylamine neoblates replaced in ortho with a substituent from NHSS CfT (CH2) X - (CH2), N (R2) (R6), - (CH2), (Re), - (CH2OOL, , ORe), 00 (O) 2, - (CH 2) r 0 C (O) R 6, - (CH 2), C (O) R 2, iCH 2) C (O) R 6 - (CH 2) r C (O) N (R 2) ) (R 2), - (CH 2) r C (O) N (R 2) (R 6). - (CH 2) r N (R 2) - R 2 - (C H 2) r N (R 2) C (O) R 6. - (CH 2) r N (R 6) C (O) R 2, - (CH 2) r N (R 2) C (O) OR 2, - (CH 2) r N (R 2) C (O) 0 R 6. - (CH 2) r N (R 6) C (O) O R 21 - (CH 2): N (S) C (O) O R - - (CH 2) r N (R 2) C (O) N (R 2) (R e) - 0 - N (R 2) (R 2). - (CH 2) r N (R 6) C (O) N (R 2) (R 6), - (CH 2) r N (R 2) SO 2 R 6, R 2 (R 2) -SO 2 R 2 - (CH 2) r N (R 6) SO2R2, - (CH2), N (R6) SO2R6, - (CH2) rOC (O) N (R2) (R6), - (CH2) r10C (O) N (R2) (R2), - (CH2) rSO2N (R 2) (R 6), - (CH 2) r SO 2 N (R 2) (R 2), - (CH 2) r SO 2 NHC (O) R 6, - (CH 2) r SO 2 NHC (O) R 2, - (CH 2) r SO 2 NHC (O) 0 R 6, - (CH2) rSO2NHC (O) 0R2, - (CH2) rCONHSO2R6, - (CH2) rC0NHSO2R2 > - (CH2) rS (O) mR6 and - (CH2) rS (O) mR2; R 3a is hydrogen or C 1-4 alkyl; X taken from the row: hydrogen, groups 20 LV 11525 21 Υ ņemts no rindas: ūdeņraža atoms, Ci.8alkilgrupa, -(CH2)t-arilgrupa, -(CH2)q-Cs^cikloalkilgrupa, -(CH2)q-K-Ci.6alkilgrupa, -(CH2)q-K-(CH2)t-arilgrupa, -(CH2)q-K-(CH2)t-C5-6cikloalkilgrupa, kur K ir -S(0)m-, bet alkilgrupas neobligāti aizvietotas ar hidroksilgrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci^alkilgrupu vai 1H-tetrazol-5-ilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, tiazolilgrupa, imidazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa vai tiofenilgrupa, kas neobligāti aizvietotas ar 1-2 halogēna atomiem, 1-2 -OR2 grupām, -C(0)0R2, 1-2 Ci^alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; A ņemts no rindas: Ur ru .C/H3 “30^^0113 H3c CH3H3C CH3 9h3 £ T vV vV CH, H.,C, ,CH,21 Υ taken from the series: hydrogen, C 1-8 alkyl, - (CH 2) t -aryl, - (CH 2) q -C 5 -C 6 cycloalkyl, - (CH 2) q K -C 1-6 alkyl, - (CH 2) q K - (CH 2) t-aryl, - (CH2) qK- (CH2) t-C5-6cycloalkyl, where K is -S (O) m-, but alkyl is optionally substituted with hydroxyl, carboxyl, -C (O) NH2 or -C (0) ) 0-C 1-6 alkyl or 1H-tetrazol-5-yl, wherein aryl is phenyl, naphthyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl optionally substituted with 1-2 halogens, 1-2 For -OR2 groups, -C (O) 0R2, 1-2C1-4alkyl, -S (O) mR2 or 1H-tetrazol-5-yl; A is taken from: Ur ru. C / H 3 '30 µl 0113 H 3c CH 3 H 3 C CH 3 9h 3 T T vV vV CH, H, C,, CH, R4 un R5 neatkarīgi viens no otra ņemti no rindas: -H -ch3 -ch2ch3 /γ OH CH, CH2OH OH R6 ir ūdeņraža atoms, Ci-ealkilgrupa vai -(CH2)v-arilgrupa, kur alkilgrupas un (CH2)v grupas neobligāti aizvietotas ar halogēna atomu, -0(R2), - N(R2)(R2), C3-6Cikloalkilgrupu, , 1H-tetrazol-5-ilgrupu, -C(0)OR2, -C(0)N(R2)(R2), -S02N(R2)(R2) vai -N(R2)C(0)N(R2)(R2), pie tam arilgrupa ir viena no rindas: N ~~ΐ NH N=NR4 and R5 are independently selected from the group consisting of -H-CH3-CH2CH3 / γ OH CH, CH2OH OH R6 is hydrogen, C1-6alkyl, or - (CH2) v-aryl, wherein alkyl and (CH2) v are optional substituted with halogen, -O (R 2), - N (R 2) (R 2), C 3-6 cycloalkyl,, 1H-tetrazol-5-yl, -C (O) OR 2, -C (O) N (R 2) ( R 2), -SO 2 N (R 2) (R 2) or -N (R 2) C (O) N (R 2) (R 2), wherein the aryl group is one of the following: N '- NH NH = N ^ / H >=o n-n H ’ H N fJ tf /, S-N N=n L N- O-N U n-n H O-N 22 LV 11525 vai tās pozicionālais izomērs, pie tam šī grupa neobligāti aizvietota ar C-i^alkilgrupu, -N(R2)(R2) vai hidroksilgrupu; m ir 0,1 vai 2; q ir 0 vai 1; r ir 0,1, 2 vai 3; t ir 0 vai 1; v ir 0 vai 1; kā arī šī savienojuma farmaceitiski pieņemamās salis un individuāli diastereomēri.Λ / H = = n n H HN fJ t f /, SN N = n L N-ON U nn H ON 22 LV 11525 or its positional isomer, optionally substituted with C 1-6 alkyl, -N (R 2); ) (R 2) or hydroxy; m is 0.1 or 2; q is 0 or 1; r is 0,1, 2 or 3; t is 0 or 1; v is 0 or 1; as well as pharmaceutically acceptable fractions and individual diastereomers of this compound. 11. Stereospecifiski raksturots savienojums pēc 7. punkta ar formulu: Η Η O R, = I II ,4 Rļ—j-N-C-A-N C=0 R5 (ChJIS Μ-Χ R3 Y kurā Ri, R3l R4, R5, A, X, Y un n ir ar 7. punktā minētajām nozīmēm. 12. Savienojums pēc 7. punkta, kas ņemts no rindas:11. A stereospecifically characterized compound according to claim 7 having the formula: Η Η OR, = I II, 4 R16 - jNCAN C = 0 R5 (ChJIS Μ-Χ R3 Y wherein R1, R3l R4, R5, A, X, Y and n have the meanings referred to in paragraph 7. 12. The compound of paragraph 7 taken from the line: 2323 cis dļ, cļs d2, trans dļ, trans d2cis dl, d2 d trans, trans d2 cis dļ, cjs d?, trans dļ. trans d2cis d, cjs d ?, trans. trans d2 24 LV 1152524 EN 11525 cis dļ. cis d2. trans dļ. trans d2cis on. cis d2. trans. trans d2 cis dļ. cis d2. trans dļ. trans d2cis on. cis d2. trans. trans d2 2525 IZIZ 26 LV 1152526 LV 11525 kā arī tā farmaceitiski pieņemamām sārīm un individuāliem diastereomeriem, ja tādi jau nav sevišķi norādīti.as well as its pharmaceutically acceptable alkali and individual diastereomers, if not already specifically indicated. 13. Savienojums ar formulu (Cl) Η H 0 R4 I II / R1 N-C-A-N C=° \ (CHiiS Y kurā: Ri ņemts no rindas: Ci-ioalkilgrupa, arilgrupa, aril-C^alkilgrupa, C3-7cikloalkil-Cļ^alkilgrupa, Ci-5alkil-K-Ci.5alkilgrupa, aril-Co-salkil-K-Cļ-salkilgrupa, C3.7 ciklo-alkil-Co-salkil-K-Ci.salkilgrupa, kur K ir -O-, -S(0)m-, -N(R2)C(0)-, -OC(O)-, -C(0)0-, -CR2=CR2- vai 'CSC-, bet arilgrupa ņemta no rindas: 27 fenilgrupa, naftilgrupa, indolilgrupa, azaindolilgrupa, piridinilgrupa, benzotienilgrupa, benzofuranilgrupa, tiazolilgrupa, benzimidazolilgrupa, pie tam R2 un alkilgrupas neobligāti aizvietotas ar 1 - 9 halogēna atomiem, -S(0)mR2a, 1 - 3 -OR2a vai -C(0)0R2a grupām, bet arilgrupa neobligāti aizvietota ar 1 - 3 Ci-6alkilgrupām, 1 - 3 halogēna atomiem, 1 - 2 -OR2 grupām, metilēndioksigrupām vai -S(0)mR2 grupām; 1-2 trifluormetilgrupām, trifluormetoksigrupām, nitrogrupām vai grupām: -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)(R2), -S02N(R2)(R2), -N(R2)S02-C6H5, -N(R2)S02R2 vai 1H-tetrazol-5-ilgrupām; R2 ņemts no rindas: ūdeņraža atoms, Ci-6alkilgrupa, C3-7cikloalkilgrupa, pie tam , ja pie viena atoma pievienotas divas Ci-6alkilgrupas, tās neobligāti savienotas, veidojot C3.8ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a, kur R3a ir ūdeņraža atoms vai Ci.6alkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; R2a ir ūdeņraža atoms vai Ci-6alkilgrupa, kas neobligāti aizvietota ar hidroksilgrupu; X ņemts no rindas: ūdeņraža atoms, ciāngrupa, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)rarilgrupa, -(CH2)qN(R2)S02(CH2)t-arilgrupa, -(CH2)q-N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)rarilgrupa, -(CH2)qN(R2)-C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)rarilgrupa, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)t-arilgrupa, -(CH2)qOR2, -(CH2)q0C(0)R2l -(CH2)q0C(0)(CH2)rarilgrupa, -(CH2)q0C(0)N(R2)(CH2)rarilgrupa, -(CH2)qO-C(0)N(R2)(R2), -(CH2)qC(0)R2, -(CH2)qC(0)(CH2)rarilgrupa, -(CH2)qN(R2)-C(0)0R2, -(CH2)qN(R2)S02N(R2)(R2), -(CH2)qS(0)mR2 un -(CH2)qS(0)m(CH2)t-arilgrupa, kur R2, (CH2)q un (CH2)t neobligāti aizvietoti ar 1 - 2 Ci^alkilgrupam, hidroksilgrupu, Ci-4alkoksigrupu, karboksilgrupu, -CONH2, -S(0)mCH3, -C(0)0-CMalkilgrupu, 1H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa, naftilgrupa, piridilgrupa, tiazolilgrupa vai 1 H-tetrazol-5-ilgrupa, kuras neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 grupām -OR2i -C(0)N(R2)(R2), -C(0)0R2, 1 - 3 Ci.4alkilgrupām, -S(0)mR2 vai 1 H-tetrazol-5-ilgrupu; Y ņemts no rindas: ūdeņraža atoms, Ci.ioalkilgrupa, -(CH2)rarilgrupa, -(CH2)q-C3-7Cikloalkilgrupa, -(CH2)q-K-Ci-6alkilgrupa, -(CH2)q-K-(CH2)rarilgrupa, -(CH2)q-K-(CH2)rC3.7cikloalkilgrupa, kas cikloalkilgrupā satur -O-, >NR2 vai -S-, -(CH2)q-K-(CH2)t-C3-7Cikloalkilgrupa, kur K ir -O-, -S(0)m-, -C(0)NR2-, -CH=CH-, -C^C-, -N(R2)C(0)-, -C(0)NR2-, -C(0)0- vai -OC(O)-, bet alkilgrupas, R2, (CH2)q un (CH2)t neobligāti aizvietotas ar CMalkilgrupu, hidroksilgrupu, CMalkoksigrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci.4alkilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, tiazolilgrupa, imidazolilgrupa, indolilgrupa, pirimidinilgrupa, tiadiazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa, tiofenilgrupa, hinolinilgrupa, pirazinilgrupa vai izotiazolilgrupa, kas neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 -OR2 grupām, -C(0)0R2, -C(0)N(R2)(R2), nitrogrupu, ciāngrupu, benzilgrupu, 1-3 Ci^alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu, ar tādu noteikumu, ka, ja X ir ūdeņraža atoms, tad Y nav ūdeņraža atoms; 28 LV 11525 R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci^alkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1 - 3 hidroksilgrupām, 1 - 3 Ci-i0alkan-oiloksigrupām, 1 - 3 Ci.6alkoksigrupām, fenilgrupu, fenoksigrupu, 2-furilgrupu, Ci.6alkoksikarbonilgrupu, -S(0)m-Ci-6alkilgrupu, vai arī R4 un R5 abi kopā var veidot grupu -(CH2)d-La-(CH2)e-, kurā La ir -C(R2)2-, -O-, -S(0)m- vai -N(R2)-, bet d un e neatkarīgi viens no otra ir 1 - 3, un R2 nozīmes ir jau minētās; Air; — (CH2)x-C-(CH2)y— R7a vai —Z~ (CH2)x-c - (CH2)— ^7a kur x un y neatkarīgi viens no otra ir 0, 1, 2 vai 3; Z ir -N(R6a)- vai -O-, kur R6a ir ūdeņraža atoms vai C^alkilgrupa; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, Ci.6alkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2, -S(0)mR2, -C(0)0-Ci.6alkilgrupu, C3_7cikloalkilgrupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arīR7 un R7a neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5l veidojot alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, pie tam tiltiņš var saturēt no 1 līdz 5 oglekļa atomus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3.7cikloalkilgrtipu, ar tādu noteikumu, ka tad, kad X vai Y ir neaizvietota fenilgrupa un R4 un R5 ir ūdeņraža atoms, R7 un R7a nav neaizvietota Cļ-ealkilgrupa; m ir 0, 1 vai 2; n ir 1, 2 vai 3; q ir 0, 1,2,3 vai 4; t ir 0, 1,2 vai 3; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuāli diastereomēri.13. A compound of formula (C 1) H 0 R 4 I / R 1 NCAN C = ° (CH 2 S Y wherein R 1 is taken from C 1 -C 10 alkyl, aryl, aryl-C 1-6 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl) , C 1-5 alkyl-K-C 1-5 alkyl, aryl-Co-salkyl-K-C 1-6 alkyl, C 3-7 cycloalkyl-Co-salkyl-K-C 1-6 alkyl, wherein K is -O-, -S ( 0) m-, -N (R 2) C (O) -, -OC (O) -, -C (O) 0-, -CR 2 = CR 2 - or 'CSC-, but aryl is selected from the group consisting of: 27 phenyl; naphthyl, indolyl, azaindolyl, pyridinyl, benzothienyl, benzofuranyl, thiazolyl, benzimidazolyl, R2 and alkyl optionally substituted with 1 to 9 halogens, -S (O) mR2a, 1-3 -OR2a or -C (O) 0R2a groups but aryl is optionally substituted with 1 to 3 C 1-6 alkyl groups, 1 to 3 halogens, 1 to 2 -OR 2 groups, methylenedioxy groups, or -S (O) m R 2 groups, 1-2 trifluoromethyl groups, trifluoromethoxy groups, nitro groups or groups: -N ( R2) C (O) (R2), -C (O) 0R2, -C (O) N (R2) (R2), -SO2N (R2) (R2), -N (R2) SO2-C6H5, -N (R2) SO2R2 or 1H etrazol-5-long; R2 is taken from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, where two C1-6 alkyl groups are attached to one atom, they are optionally bonded to form C3.8, optionally including oxygen or sulfur. an atom or group > NR3a, wherein R3a is hydrogen or C1-6alkyl optionally substituted by hydroxy; R 2a is hydrogen or C 1-6 alkyl optionally substituted with hydroxy; X taken from hydrogen: cyano, - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) raryl, - (CH2) qN (R2) S02 (CH2) t -Aryl, - (CH2) qN (R2) SO2R2, - (CH2) qN (R2) C (O) N (R2) (CH2) raryl, - (CH2) qN (R2) -C (0) ) N (R2) (R2), - (CH2) qC (O) N (R2) (R2), - (CH2) qC (O) N (R2) (CH2) raryl, - (CH2) qC (O) 0R2, - (CH2) qC (O) 0 (CH2) t -aryl, - (CH2) qOR2, - (CH2) qC (O) R2l - (CH2) qC (O) (CH2) raryl, - (CH2) q0C (0) N (R2) (CH2) raryl, - (CH2) qO-C (O) N (R2) (R2), - (CH2) qC (O) R2, - (CH2) qC (0) ( CH2) raryl, - (CH2) qN (R2) -C (O) 0R2, - (CH2) qN (R2) SO2N (R2) (R2), - (CH2) qS (O) mR2 and - (CH2) qS (0) m (CH 2) t -aryl, wherein R 2, (CH 2) q and (CH 2) t are optionally substituted with 1 to 2 C 1-4 alkyl, hydroxy, C 1-4 alkoxy, carboxyl, -CONH 2, -S (O) mCH 3 , -C (O) O-CMalkyl, 1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl optionally substituted with 1 to 3 halogens, 1 - 3 for -OR2i -C (O) N (R2) (R2), -C (O) 0R2, 1-3C1-4alkyl, -S (O) mR2 or 1 H-tetrazol-5-yl; Y is taken from the group: hydrogen, C1-10alkyl, - (CH2) raryl, - (CH2) q-C3-7Cycloalkyl, - (CH2) qK-C1-6 alkyl, - (CH2) qK- (CH2) raryl, - (CH2) qK- (CH2) rC3.7cycloalkyl containing -O-, cycloalkyl, -O-, NR2 or -S-, - (CH2) qK- (CH2) t-C3-7Cycloalkyl, where K is -O-, - S (O) m-, -C (O) NR 2 -, -CH = CH-, -C 1 -C-, -N (R 2) C (O) -, -C (O) NR 2 -, -C (0) ) 0- or -OC (O) -, but alkyl, R2, (CH2) q and (CH2) t are optionally substituted with CMalkyl, hydroxyl, CMalkoxy, carboxyl, -C (O) NH2 or -C (O) 0- C 1-4 alkyl, wherein aryl is phenyl, naphthyl, pyridinyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl optionally substituted with 1-3 halogens, 1-3 -OR2 groups, -C (O) 0R2, -C (O) N (R2) (R2), nitro, cyano, benzyl, 1-3C1-6alkyl, -S (0) ) mR2 or 1H etrazol-5-yl, provided that when X is hydrogen then Y is not hydrogen; 28 EN 11525 R4 and R5 independently of one another are hydrogen, C1-6alkyl, optionally substituted with 1 to 5 halogens, 1-3 hydroxyl groups, 1-3C 1-10 alkanalkoxy groups, 1-3C 1-6 alkoxy groups, phenyl, Phenoxy, 2-furyl, C 1-6 alkoxycarbonyl, -S (O) m -C 1-6 alkyl, or R 4 and R 5 together may form a group - (CH 2) d -L- (CH 2) e - wherein La is -C (R 2) 2-, -O-, -S (O) m - or -N (R 2) -, but d and e are independently 1 to 3, and R 2 has the same meanings; Air; - (CH 2) x -C- (CH 2) y -R 7a or -Z ~ (CH 2) x-c - (CH 2) - 7 7a wherein x and y are independently 0, 1, 2 or 3; Z is -N (R 6a) - or -O-, wherein R 6a is hydrogen or C 1-4 alkyl; R7 and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-6alkyl optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S (O) mR2, -C (O) 0 -C 1-6 alkyl, C 3-7 cycloalkyl, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 7 and R 7a are independently joined to one or both R 4 and R 5l to form alkylene bridges between the terminal nitrogen atom and the R7 and R7a alkyl moieties, wherein the bridge may contain from 1 to 5 carbon atoms, or R7 and R7a may be joined together to form a C3-7cycloalkyl ring, provided that when X or Y is unsubstituted phenyl and R 4 and R 5 are hydrogen, R 7 and R 7a are not unsubstituted C 1-6 alkyl; m is 0, 1 or 2; n is 1, 2 or 3; q is 0, 1,2,3 or 4; t is 0, 1, 2 or 3; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 14. Savienojums pēc 13. punkta, kurā: R1 ir ņemts no rindas: Ci-ioalkilgrupa, aril-Ci^alkilgrupa, C3.6cikloalkil-Ci.4alkilgrupa, CMalkil-K-Ci.2alkilgrupa, aril-Co-2alkil-K-Ci_2alkilgrupa, C3.7cikloalkil-Co-2alkil-K-Ci.2alkilgrupa, kur K ir -0-, -S(0)m-, -OC(O)- vai -C(0)0-, alkilgrupas neobligāti aizvietotas ar 1 - 7 halogēna atomiem, -S(0)mR2, 1 - 3 -OR2 vai -C(0)OR2 grupām, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, indolilgrupa, piridinilgrupa, benzotienilgrupa vai 29 benzofuranilgrupa, kas neobligāti aizvietota ar 1 - 2 Ci^alkilgrupām, 1-2 halogēna atomiem, 1-2 -OR2 grupām vai metilēndioksigrupām, -S(0)mR2 grupu vai -C(0)0R2 grupu; R2 ņemts no rindas: ūdeņraža atoms, Ci-ealkilgrupa, C3-7Cikloalkilgrupa, pje tam, ja pie viena atoma pievienotas divas Ci^alkilgrupas, tās neobligāti savienotas, veidojot C4-7ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; R3a ir ūdeņraža atoms vai Ci-4alkilgrupa; X ņemts no rindas: ūdeņraža atoms, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)t-arilgrupa, -(CH2)qN(R2)S02(CH2)rarilgrupa, -(CH2)q-N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)q-arilgrupa, -(CH2)qN(R2)-C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)rarilgrupa, -(CH2)qC(0)0R2, -(CH2)qC(0)0(CH2)t-arilgrupa, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)rarilgrupa, -(CH2)qN(R2)-C(0)0R2l -(CH2)qS(0)mR2 un -(CH2)qS(0)m(CH2)t-arilgrupa, kur R2 neobligāti aizvietots ar hidroksilgrupu, karboksilgrupu, -CONH2, -S(0)mCH3, -C(0)0-Ci^alkilgrupu. 1 H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa vai 1 H-tetrazol-5-ilgrupa, kuras neobligāti aizvietotas ar 1 - 2 halogēna atomiem, 1-2 grupām -OR2, -C(0)NH2, -C(0)0R2i 1 - 3 C^alkilgrupām, -S(0)mR2 vai 1 H-tetrazol-5-ilgrupu; Y ņemts no rindas: ūdeņraža atoms, Ci-8alkilgrupa, -(CH2)rarilgrupa, -(CH2)q-Cs-ecikloalkilgrupa, -(CH2)q-K-C1-6alkilgrupa, -(CH2)q-K-(CH2)rarilgrupa, -(CH2)q-K-(CH2)rC3-7Cikloalkilgrupa, kas cikloalkilgrupā satur -O-, >NR2 vai -S-, -(CH2)q-K-(CH2)t-C5.6cikloalkilgrupa, kur K ir -O- vai -S(0)m-, bet alkilgrupas neobligāti aizvietotas ar hidroksilgrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci-4alkilgrupu vai 1H-tetrazol-5-ilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, 1H-tetrazol-5-ilgrupa, tiazolilgrupa, imidazolilgrupa, pirimidinilgrupa, tiadiazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa vai tiofenilgrupa, kas neobligāti aizvietotas ar 1 - 3 halogēna atomiem, 1 - 3 -OR2 grupām, 1 - 2 -N(R2)(R2) grupām, -C(0)0R2, -C(0)N(R2)(R2), ciāngrupu, 1 - 2 Ci^alkilgrupām, benzilgrupu, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu, ar tādu noteikumu, ka tad, kad X ir ūdeņraža atoms, Y nav ūdeņraža atoms; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Cļ^alkilgrupa, neobligāti aizvietota ar 1 - 5 halogēna atomiem, 1-3 hidroksilgrupām, -S(0)m-Ci.6alkilgrupu vai fenilgrupu; Air: (CH2)x—C — 7a R kurx ir 0 vai 1; 30 LV 11525 R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, trifluormetilgrupa, fenilgrupa, Ci.6alkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2, -S(0)mR2, Cs^cikioalkil-grupu, -N(R2)(R2), -C(0)N(R2)(R2), vai arī R7 un R7a neatkarīgi viens no otra ir savienoti ar vienu vai abām grupām R4 un R5, veidojot alkilēngrupu tiltiņus starp galējo slāpekļa atomu un R7 un R7a grupu alkildaļām, pie tam tiltiņš var saturēt no 1 līdz 5 oglekļa atomus, vai arī R7 un R7a var būt savienoti savā starpā, veidojot C3cikloalkilgrupu, ar tādu noteikumu, ka tad, kad X vai Y ir neaizvietota fenilgrupa, bet R4 un R5 ir ūdeņraža atoms, R7 un R7a nav neaizvietota Ci.6alkilgrupa; m ir 0, 1 vai 2; n ir 2; q ir 0, 1,2 vai 3; t ir 0, 1, 2 vai 3; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuāli diastereomēri.The compound of claim 13, wherein: R 1 is selected from the group consisting of: C 1-10 alkyl, arylC 1-6 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 1-4 alkyl-C 1 -C 2 alkyl, aryl-Co-2-alkyl-K- C1-2alkyl, C3-7cycloalkyl-Co-2alkyl-K-C1-2alkyl, where K is -O-, -S (O) m-, -OC (O) - or -C (O) 0-, alkyl optionally substituted with 1-7 halogen atoms, -S (O) mR2, 1-3 -OR2 or -C (O) OR2, but aryl is selected from phenyl, naphthyl, indolyl, pyridinyl, benzothienyl or 29 benzofuranyl optionally substituted with 1 to 2 C 1-6 alkyl groups, 1-2 halogen atoms, 1-2 -OR 2 groups or methylenedioxy groups, -S (O) m R 2 group or -C (O) 0 R 2 group; R2 is taken from the group consisting of: hydrogen, C1-6alkyl, C3-7Cycloalkyl, when two C1-4alkyl atoms are attached to one atom, they are optionally bonded to form a C4-7 ring optionally containing an oxygen or sulfur atom or a group >NR3a; R 3a is hydrogen or C 1-4 alkyl; X taken from hydrogen: - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) t -Aryl, - (CH2) qN (R2) S02 (CH2) raryl, - (CH2) qN (R2) SO2R2, - (CH2) qN (R2) C (O) N (R2) (CH2) q -aryl, - (CH2) qN (R2) -C (O) ) N (R2) (R2), - (CH2) qC (O) N (R2) (R2), - (CH2) qC (O) N (R2) (CH2) raryl, - (CH2) qC (O) 0R2, - (CH2) qC (O) 0 (CH2) t -aryl, - (CH2) qC (O) R2, - (CH2) qC (O) (CH2) raryl, - (CH2) qN (R2) - C (O) 0R2 - (CH2) qS (O) mR2 and - (CH2) qS (O) m (CH2) t -aryl, wherein R2 is optionally substituted with hydroxy, carboxyl, -CONH2, -S (O) mCH3, -C (O) O-C 1-4 alkyl. 1 H-tetrazol-5-yl, but aryl is phenyl, naphthyl, pyridinyl or 1H-tetrazol-5-yl optionally substituted with 1 to 2 halogens, 1-2 groups -OR 2, -C (O) NH 2 , -C (O) 0R2i 1-3C1alkyl, -S (O) mR2 or 1H-tetrazol-5-yl; Y is selected from the group consisting of: hydrogen, C 1-8 alkyl, - (CH 2) raryl, - (CH 2) q -C 5 -C 6 cycloalkyl, - (CH 2) q K -C 1-6 alkyl, - (CH 2) q K - (CH 2) raryl, - (CH2) qK- (CH2) rC3-7Cycloalkyl, which contains cycloalkyl -O-, > NR2 or -S-, - (CH2) qK- (CH2) t-C5.6cycloalkyl, where K is -O- or - S (O) m-, but alkyl optionally substituted with hydroxy, carboxyl, -C (O) NH 2 or -C (O) O-C 1-4 alkyl or 1H-tetrazol-5-yl, wherein aryl is phenyl, naphthyl, pyridinyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl optionally substituted with 1-3 halogens, 1-3 -OR2 groups, 1-2-N (R2) ) (R 2) groups, -C (O) 0 R 2, -C (O) N (R 2) (R 2), cyano, 1 to 2 C 1-4 alkyl, benzyl, -S (O) m R 2, or 1H-tetrazol-5 longitudinal, with the proviso that when X is hydrogen, Y is not hydrogen; R 4 and R 5 are independently hydrogen, C 1-4 alkyl optionally substituted with 1 to 5 halogens, 1-3 hydroxyl groups, -S (O) m -C 1-6 alkyl or phenyl; Air: (CH2) x-C-7a R kurx is 0 or 1; 30 EN 11525 R7 and R7a independently of one another are hydrogen, trifluoromethyl, phenyl, C1-6alkyl, optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S (O) mR2, Cs2cycloalkyl -Group, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 7 and R 7a are independently attached to one or both R 4 and R 5 to form alkylene bridges between the extreme nitrogen atoms and R7 and R7a alkyl atoms, wherein the bridge may contain from 1 to 5 carbon atoms, or R7 and R7a may be bonded to each other to form a C3-cycloalkyl group, provided that when X or Y is unsubstituted phenyl, but R 4 and R 5 are hydrogen, R 7 and R 7a are not unsubstituted C 1-6 alkyl; m is 0, 1 or 2; n and 2; q is 0, 1, 2 or 3; t is 0, 1, 2 or 3; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 15. Savienojums pēc 13. punkta ar formulu (Cib)15. A compound of claim 13 having the formula (Cib) R1 ir ņemts no rindas: CM0alkilgrupa, aril-Ci-3alkilgrupa, C^cikloalkil-Ci.3alkilgrupa, aril-C0-ialkil-K-Ci.2alkilgrupa, kur K ir -O- vai -S(0)m-, bet arilgrupa ņemta no rindas: fenilgrupa, naftilgrupa, piridinilgrupa, indolilgrupa, azaindolilgrupa vai benzimidazolilgrupa, kas neobligāti aizvietota ar 1 - 2 Ci^alkilgrupām, 1-2 halogēna atomiem, 1-2 -OR2 grupām, -S(0)mR2 grupu vai -C(0)0R2 grupu; R2 ņemts no rindas: ūdeņraža atoms, Ci-6alkilgrupa, C3.7Cikloalkilgrupa, pie tam, ja pie viena atoma pievienotas divas Ci^alkilgrupas, tās neobligāti savienotas, veidojot Cs^ciklu, kas neobligāti ietver skābekļa vai sēra atomu, vai grupu >NR3a; R3a ir ūdeņraža atoms vai Ci^alkilgrupa; X ņemts no rindas: ūdeņraža atoms, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)rarilgrupa, -(CH2)qN(R2)S02(CH2)rarilgrupa, -(CH2)q- 31 N(R2)S02R2, -(CH2)qN(R2)C(0)N(R2)(CH2)t-arilgrupa, -(CH2)qN(R2)- C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)t-arilgrupa, -(CH2)qC(0)OR2, -(CH2)qC(0)0(CH2)t-arilgrupa, -(CH2)q0C(0)R2, -(CH2)q0C(0)(CH2)t-arilgrupa, -(CH2)qS(0)mR2 un -(CH2)qS(0)m(CH2)t-arilgrupa, kur R2 neobligāti aizvietots ar hidroksilgrupu, karboksilgrupu, -CONH2, -SfOjmCHa, -C(0)0-Ci-4alkilgrupu vai 1H-tetrazol-5-ilgrupu, bet arilgrupa ir fenilgrupa, naftilgrupa vai piridinilgrupa, kuras neobligāti aizvietotas ar 1 - 2 halogēna atomiem, 1-2 grupām -OR2, -C(0)0R2l 1-3 Ci-4alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu; Y ņemts no rindas: ūdeņraža atoms, Ci-ealkilgrupa, -(CH2)t-arilgrupa, -(CH2)q-C5-7Cikloalkilgrupa, -(CH2)q-K-Ci^alkilgrupa, -(CH2)q-K-(CH2)t-arilgrupa, -(CH2)q-K-(CH2)t-C5-6Cikloalkilgrupa, kur K ir -S(0)m-, bet alkilgrupas neobligāti aizvietotas ar hidroksilgrupu, karboksilgrupu, -C(0)NH2 vai -C(0)0-Ci-4alkilgrupu vai 1H-tetrazol-5-ilgrupu, pie tam arilgrupa ir fenilgrupa, naftilgrupa, piridinilgrupa, tiazolilgrupa, imidazolilgrupa, pirazolilgrupa, oksazolilgrupa, izoksazolilgrupa vai tiofenilgrupa, kas neobligāti aizvietotas ar 1-2 halogēna atomiem, 1-2 -OR2 grupām, 1-2 -N(R2)(R2) grupām, -C(0)0R2, 1 - 2 Ci-4alkilgrupām, -S(0)mR2 vai 1H-tetrazol-5-ilgrupu, ar tādu noteikumu, ka tad , kad X ir ūdeņraža atoms, Y nav ūdeņraža atoms; R4 un R5 neatkarīgi viens no otra ir ūdeņraža atoms, Ci^alkilgrupa vai Ci-3alkilgrupa, kas neobligāti aizvietota ar 1 - 2 hidroksilgrupām; A ir: l?7 (CH2)x—C— ^7a kur x ir 0 vai 1; R7 un R7a neatkarīgi viens no otra ir ūdeņraža atoms, fenilgrupa, Ci-ealkilgrupa, kas neobligāti aizvietota ar: imidazolilgrupu, fenilgrupu, indolilgrupu, p-hidroksifenilgrupu, -OR2 vai -S(0)mR2- vai arī R7 un R7a var būt savienoti savā starpā, veidojot Cadkloalkilgrupu, ar tādu noteikumu, ka tad, kad X vai Y ir neaizvietota fenilgrupa, bet R4 un R& ir ūdeņraža atoms, R7 un R7a nav neaizvietota Ci^alkilgrupa; m ir 0, 1 vai 2; q ir 0, 1,2 vai 3; t ir 0, 1,2 vai 3; kā arī šī savienojuma farmaceitiski pieņemamās sālis un individuāli diastereomēri. 32 LV 11525R 1 is selected from the group consisting of: C 1-4 alkyl, aryl-C 1-3 alkyl, C 1-4 cycloalkyl-C 1-3 alkyl, aryl-C 0 -C 6 alkyl-K-C 1-2 alkyl wherein K is -O- or -S (O) m-, aryl taken from the group: phenyl, naphthyl, pyridinyl, indolyl, azaindolyl or benzimidazolyl optionally substituted with 1 to 2 C 1-6 alkyl, 1-2 halogen atoms, 1-2 -OR 2 groups, -S (O) mR 2 or - C (O) 0R2; R2 is selected from the group consisting of: hydrogen, C1-6alkyl, C3-7cycloalkyl, where two C1-4alkyl groups are attached to one atom, they are optionally bonded to form a C2- ring optionally including an oxygen or sulfur atom or a group >NR3a; R 3a is hydrogen or C 1-4 alkyl; X taken from the series: hydrogen, - (CH2) qN (R2) C (O) R2, - (CH2) qN (R2) C (O) (CH2) raryl, - (CH2) qN (R2) S02 (CH2) ) Raryl, - (CH2) q-31N (R2) SO2R2, - (CH2) qN (R2) C (O) N (R2) (CH2) t -aryl, - (CH2) qN (R2) - C ( 0) N (R 2) (R 2), - (CH 2) q C (O) N (R 2) (R 2), - (CH 2) q C (O) N (R 2) (CH 2) t -aryl, - (CH 2) q C (O) OR 2, - (CH 2) q C (O) 0 (CH 2) t -aryl, - (CH 2) q CO (O) R 2, - (CH 2) q C (O) (CH 2) t -aryl, - (CH 2) qS (0) mR2 and - (CH2) qS (O) m (CH2) t -aryl, wherein R2 is optionally substituted with hydroxy, carboxyl, -CONH2, -SfOjmCHa, -C (O) 0-C1-4alkyl or 1H- tetrazol-5-yl, but aryl is phenyl, naphthyl or pyridinyl optionally substituted with 1 to 2 halogens, 1-2 groups -OR2, -C (O) 0R2l 1-3C1-4alkyl, -S (0) mR2 or 1H-tetrazol-5-yl; Y is taken from the group: hydrogen, C1-6alkyl, - (CH2) t-aryl, - (CH2) q-C5-7Cycloalkyl, - (CH2) qK-C1-6 alkyl, - (CH2) qK- (CH2) t -aryl, - (CH2) qK- (CH2) t-C5-6Cycloalkyl, where K is -S (O) m-, but alkyl is optionally substituted with hydroxy, carboxyl, -C (O) NH2 or -C (O) 0-C 1-4 alkyl or 1H-tetrazol-5-yl, wherein aryl is phenyl, naphthyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl optionally substituted with 1-2 halogens, 1-2 - OR2 groups, 1-2 -N (R2) (R2) groups, -C (O) 0R2, 1-2C1-4alkyl, -S (O) mR2 or 1H-tetrazol-5-yl, with the proviso that when X is hydrogen, Y is not hydrogen; R4 and R5 are independently from each other hydrogen, C1-6alkyl or C1-3alkyl optionally substituted with 1 to 2 hydroxyl groups; A is: 1-7 (CH2) x-C 1-7a wherein x is 0 or 1; R7 and R7a independently of one another are hydrogen, phenyl, C1-6alkyl optionally substituted with: imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2 or -S (O) mR2- or R7 and R7a may be bonded by forming a Cadloalkyl group, provided that when X or Y is unsubstituted phenyl, R4 and R & is hydrogen, R7 and R7a are not unsubstituted C1-6 alkyl; m is 0, 1 or 2; q is 0, 1, 2 or 3; t is 0, 1, 2 or 3; as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 32 EN 11525 16. Savienojums pēc 13. punkta ar formulu (Clc) Η H R “I ,Π4 Rļ—C—N C-A NL i " R5 c=o o16. A compound according to claim 13 having the formula (Clc) Η H R ', ļ4 Rl — C-N C-A NL i " R5 c = o o kurā: R1 ņemts no rindas:where: R1 is taken from the row: CH2-CH2- MeOMeO CH2-CH2- H -N"CH2H -N " CH2 H CH2-H CH2- ch2-ch2- .ChU.ChU .ch2- .ch2- HO.ch2- .ch2- HO vai to pozicionālajiem izomēriem, ja tie jau nav sevišķi norādīti; 33 X ņemts no rindas: ūdeņraža atoms unor their positional isomers, if not already specifically indicated; 33 X taken from the row: hydrogen atom and 34 LV 11525 Y ņemts no rindas: ūdeņraža atoms un H3C34 EN 11525 Y taken from the row: hydrogen and H3C H,C CH3H, C CH 3 1-3 halogen-ļf-CH2- ^ CH2- N1-3 halo-α-CH 2 --CH 2 --N *N ^-CH2-* N ^ -CH2- N S- ^^CH3 ^ν*όη2- s-N S- ^^ CH3 ^ ν * όη2- s- ΊΜ S N <ΊΜ S N < H3C.N /K 'jl \ s N <H3C.N / K 'n < N. < jCHr ς"ΌΗοN. < jCHr ς " ΌΗο 2’2 ' vai to pozicionālajiem izomēriem, ja tie jau nav sevišķi norādīti, ar noteikumu, ka tad, kad X ir ūdeņraža atoms, Y nav ūdeņraža atoms; 35 A ir ņemts no rindas: H3C. , ^CH3 H3C^CH3 -CH3 HaC CH3 ĢH3 .^ vV w vV xV HaC, CH, .CH,or their positional isomers, if not specifically indicated, provided that when X is hydrogen, Y is not hydrogen; 35 A is taken from H3C. , CH 3 H 3 H 3 CH 3 CH 3 -CH 3 HaC CH 3 H 3 ^ vV w vV xV HaC, CH, .CH, CH2OH OH R4 un R5 neatkarīgi viens no otra ņemti no rindas: -H -CH3 -CH2CH3 OH kā arī šī savienojuma farmaceitiski pieņemamās salis un individuālie diastereomēri.CH 2 OH OH R 4 and R 5 are independently selected from the group consisting of -H-CH 3 -CH 2 CH 3 OH as well as pharmaceutically acceptable salts and individual diastereomers of this compound. 17. Stereospecifiski raksturots savienojums pēc 13. punkta ar formulu Η Η O R4 — I II > * R1—j—N-C-A-N C = 0 R5 .N (CH2)n —X Y kurā Ri, R4, R5, A, X, Y un n ir tādi, kādi tie minēti 13. punktā. 36 LV 1152517. A stereospecifically characterized compound according to claim 13 having the formula Η Η O R4 - I II > * R 1 - j - N-C-A-N C = O R 5 .N (CH 2) n —X Y wherein R 1, R 4, R 5, A, X, Y and n are as defined in claim 13. 36 LV 11525 18. Savienojums pēc 13. punkta, kas ņemts no rindas:18. The compound of claim 13, taken from the line: 3737 ΟΕί τ wNHEt1ΓοΟΕί τ wNHEt1Γο Ο Ν 38 LV 11525LV Ν 38 LV 11525 OEtOEt ΥΥ NN OEtOEt N HN H Η H .^N C=0 0N. NHMe MyΗ H. N N = 0 0N. NHMe My OEtOEt 0 \^N0 N \^NN 0 nh2 s0 nh2 s \^NN 3939 40 LV 1152540 LV 11525 kā arī šo savienojumu farmaceitiski pieņemamām sālīm un individuāliem diastereomēriem, ja tādi jau nav sevišķi norādīti.as well as pharmaceutically acceptable salts and individual diastereomers of these compounds, if not already specifically indicated. 19. Kompozīcija augšanas hormona endogēnās veidošanās vai izdalīšanās palielināšanai cilvēkiem un dzīvniekiem, kas atšķiras ar to, ka tā satur inertu nesēju un iedarbīgu daudzumu savienojuma pēc 1. punkta.19. A composition for increasing endogenous growth or release of growth hormone in humans and animals, characterized in that it comprises an inert carrier and an effective amount of a compound of claim 1. 20. Kompozīcija augšanas hormona endogēnās veidošanās vai izdalīšanās palielināšanai cilvēkiem un dzīvniekiem, kas atšķiras ar to, ka tā satur inertu nesēju, iedarbīgu daudzumu savienojuma pēc 1. punkta un vēl papildus pievienotu citu augšanas hormona izdalīšanās veicinātāju.A composition for increasing endogenous growth or release of growth hormone in humans and animals, characterized in that it contains an inert carrier, an effective amount of a compound of claim 1 and further addition of another growth hormone release promoter. 21. Kompozīcija pēc 20. punkta, kas atšķiras ar to, ka papildus pievienotais augšanas hormona izdalīšanās veicinātājs ir ņemts no rindas: augšanas hormona izdalīšanos veicinošais peptīds GHRP-6, augšanas hormona izdalīšanos veicinošais peptīds GHRP-2, augšanas hormona izdalīšanos veicinošais peptīds GHRP-1, savienojums B-HT920, augšanas hormona izdalīšanos veicinošais faktors, augšanas hormona izdalīšanos veicinošā faktora analogs, savienojumi IGF-1 un IGF-2.21. The composition of claim 20, wherein the additional growth hormone release promoter is selected from the group consisting of growth hormone secretion peptide GHRP-6, growth hormone secretion peptide GHRP-2, growth hormone secretion peptide GHRP- 1, Compound B-HT920, Growth Hormone Release Factor, Growth Hormone Release Factor Analogue, IGF-1 and IGF-2. 22. Kompozīcija osteoporozes ārstēšanai vai profilaksei, kas atšķiras ar to, ka tā satur kombināciju no bisfosfonāta un savienojuma pēc 1. punkta.A composition for the treatment or prophylaxis of osteoporosis, characterized in that it comprises a combination of a bisphosphonate and a compound of claim 1. 23. Kompozīcija pēc 22. punkta, kas atšķiras ar to, ka bisfosfonāts ir alendronāts.23. The composition of claim 22, wherein the bisphosphonate is alendronate. 24. Savienojuma pēc 1. punkta pielietojums ārstniecības līdzekļa ražošanai, kas paredzēts augšanas hormona endogēnā līmeņa palielināšanai cilvēkam vai dzīvniekiem. 41Use of a compound according to claim 1 for the manufacture of a medicament for increasing endogenous levels of growth hormone in a human or animal. 41 25. Savienojuma pēc 1. punkta pielietojums veterinārā līdzekļa ražošanai, kas paredzēts barības izmantošanas efektivitātes palielināšanai, augšanas veicināšanai, izslaukuma paaugstināšanai un skeleta stiprināšanai.Use of a compound according to claim 1 for the manufacture of a veterinary product for increasing feed efficiency, growth promotion, milk yield, and skeletal strengthening. 26. Savienojuma pēc 1. punkta pielietojums ārstniecības līdzekļa ražošanai, kas paredzēts, lai ārstētu vai profilaktētu slimību no rindas: osteoporoze; katabolisms; imūnitātes deficīts, tai skaitā slimniekiem ar pazeminātu T4/T8 šūnu attiecību; gūžas kaula lūzums; geriatriskie muskuļu un skeleta defekti; augšanas hormona deficīts bērniem un pieaugušajiem; aptaukošanās; kaheksija un olbaltumvielu zudums hronisko slimību gaitā, piemēram AIDS vai vēža slimniekiem; stāvoklis pēc smagām operācijām, brūcēm vai apdegumiem.26. The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a disease of the sequence: osteoporosis; catabolism; immune deficiency, including patients with reduced T4 / T8 cell ratio; hip fracture; geriatric muscle and skeletal defects; growth hormone deficiency in children and adults; obesity; cachexia and protein loss in chronic diseases such as AIDS or cancer patients; after severe operations, wounds or burns. 27. Savienojuma pēc 1. punkta kombinācijā ar bisfosfonātu pielietojums ārstniecības līdzekļa ražošanai, kas paredzēts osteoporozes ārstēšanai vai profilaksei.Use of a compound according to claim 1 in combination with a bisphosphonate for the manufacture of a medicament for the treatment or prevention of osteoporosis. 28. Pielietojums pēc 27. punkta, kas atšķiras ar to, ka bisfosfonāts ir alendronāts.28. The method of claim 27, wherein the bisphosphonate is alendronate. 29. Paņēmiens savienojuma pēc 1. punkta iegūšanai, kas atšķiras ar to, ka savienojumu ar formulu (4) Η H Rļ—ļ—N-H C=029. A process for the preparation of a compound according to claim 1, wherein the compound of formula (4) is H-R 1 -N-H C = O apstrada ar savienojumu (5) vai (6) O R. II .4 HO-C-A-N Rs5 9 L HO-C-A-N 6 iegūstot savienojumu ar formulu (1) vai (7)treated with compound (5) or (6) O R 4 .4 HO-C-A-N R 5 9 L HO-C-A-N 6 to give compound of formula (1) or (7) Η Η Ο I + i η y N-C-A-N C=0 Rs+ Η Ο I + i η y N-C-A-N C = 0 Rs R3 y 7 42 LV 11525 kur Rļ, R3, R4, R5 , A, W, X, Y un n ir tādi, kā minēts 1. punktā, bet L ir aizsarggrupa, kas, ja tāda ir, tiek vēlāk atšķelta, un, ja vēlams, pārvērš sāls veidā.R3 y 7 42 LV 11525 wherein R 1, R 3, R 4, R 5, A, W, X, Y and n are as defined in claim 1, and L is a protecting group, if any, which is subsequently separated, and if desired, converted into salt form. 30. Savienojums ar formulu30. A compound of formula un tā farmaceitiski pieņemamās sālis. 31. Savienojums ar formuluand a pharmaceutically acceptable salt thereof. 31. A compound of the formula 4343 32. Farmaceitiskā kompoztcija, kas atšķiras ar to, ka tā satur inertu nesēju un iedarbīgu daudzumu savienojuma pēc 30. punkta. 44Pharmaceutical composition, characterized in that it comprises an inert carrier and an effective amount of the compound of claim 30. 44
LVP-96-151A 1993-11-09 1996-05-22 Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone LV11525B (en)

Applications Claiming Priority (7)

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US14944193A 1993-11-09 1993-11-09
US16514993A 1993-12-10 1993-12-10
US17344993A 1993-12-23 1993-12-23
US08/323,988 US5492916A (en) 1993-12-23 1994-10-17 Di- and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone
US08/323,998 US5492920A (en) 1993-12-10 1994-10-17 Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone
US08/323,994 US5494919A (en) 1993-11-09 1994-10-17 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone
PCT/US1994/012816 WO1995013069A1 (en) 1993-11-09 1994-11-07 Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone

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LV11525B true LV11525B (en) 1997-02-20

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CA2175218A1 (en) 1995-05-18
EP0739204A1 (en) 1996-10-30
HU9601230D0 (en) 1996-07-29
SK56296A3 (en) 1997-02-05
EP0739204A4 (en) 2000-03-15
BG100555A (en) 1996-10-31
CZ134296A3 (en) 1996-12-11
BR9408019A (en) 1997-08-26
WO1995013069A1 (en) 1995-05-18
KR960705808A (en) 1996-11-08
FI961951A (en) 1996-05-08
PL322706A1 (en) 1998-02-16
JPH10506091A (en) 1998-06-16
LV11525A (en) 1996-10-20
FI961951A0 (en) 1996-05-08
NO961865D0 (en) 1996-05-08
CN1174504A (en) 1998-02-25
AU1172995A (en) 1995-05-29
NO961865L (en) 1996-07-08
HUT74733A (en) 1997-02-28

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