MXPA99002357A - Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases - Google Patents

Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases

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Publication number
MXPA99002357A
MXPA99002357A MXPA/A/1999/002357A MX9902357A MXPA99002357A MX PA99002357 A MXPA99002357 A MX PA99002357A MX 9902357 A MX9902357 A MX 9902357A MX PA99002357 A MXPA99002357 A MX PA99002357A
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Mexico
Prior art keywords
alkyl
compound
aryl
group
tumor cells
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MXPA/A/1999/002357A
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Spanish (es)
Inventor
F Rane Dinanath
G Taveras Arthur
George Njoroge F
K Mallams Alan
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Schering Corporation
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Publication of MXPA99002357A publication Critical patent/MXPA99002357A/en

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Abstract

Compounds of formula (1.0), their use as farnesyl transferase protein inhibitors and pharmaceutical compositions containing them are disclosed, especially compounds of formula (1.5A) wherein R1, R2 and R3 are halo, A and B are each H2, and R is as defined in the specification.

Description

USEFUL TRIKYCLIC COMPOUNDS FOR INHIBITION OF THE FUNCTION OF THE PPOTEIN G AND PAFA ZL TREATMENT OF PROLIFERATIVE DISEASES BACKGROUND WO 95/10516, published April 20, 1995 discloses useful tricyclic compounds for inhibition of farnesyl transferase protein. In view of the current interest in farnesyl transferase protein inhibitors, a welcome contribution to the technique may be the compounds used for the inhibition of farnesyl transferase protein. Such contribution is provided in this invention.
COMPENDIUM OF THE INVENTION This invention provides compounds useful for the inhibition of farnesyl transferase (PFT) protein. The compounds of this invention are represented by the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: a, b, c, od represents N or NR 9 wherein R9 is 0, CH3 or - (CH2) n? 2H where n is 1 to 3, and remaining groups a, b, c and d represent CR 1 or CR 2; or each of a, b, c, and d are independently selected from CR 1 or CR °; each R 1 and each R2 is independently selected from H, halo, -CF3, -OR10 (for example, -OCH3), -COR10, -SR10 (for example, SCH3 and -SCH2C6H5), -S (0) tR1: L (where t is 0, 1 or 2, for example, -SOCH3 and -S02CH3), -SCN, -N (R10) 2, -NR10RU, -N02, -OC (0) R10, -C02R10, -OCO2R11, -CN, -NHC (0) R10, -NHS02R10, - CONHR10, -CONHCH2CH2OH, -NR10COORU, -SRnC (0) ORU (eg, -SCH2C02CH3), -SRUN (R75) 2 where each R 75 is independently selected from H and -C (0) OR11 (e.g., -S (CH2) 2NHC (O) Ot-butyl and -S (CH2) 2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazole-5-ylthio (e.g. 5-ylthio substituted by alkyl such as l-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being substituted with halo, -OR10 or -C02R10; R and R are independently selected from the group consisting of H, R 1 and R 2, or R 3 and R 4 j represent a fused ring of saturated or unsaturated C 5 -C 7 to the benzene ring (ring III); S f) 1 c R, R, R and R are independently selected from the group consisting of H, CF3, -COR, alkyl and aryl, with alkyl or aryl being optionally substituted with -OR, SR10, -S (0) tRU -NR10COORn, -N (R10) 2, -N02, -COR10, -OCOR10, -OC02Rn, -C02R10, or OPO3R10, or R5 is combined with R6 which 7 ft represents = 0 or = S, or R is combined with R to represent = 0 or = S; R represents H, alkyl, aryl, or aralkyl (for example, benzyl); R represents alkyl or aryl; X represents N, CH or C, where C can contain an optional double bond (represented by the dotted line) to carbon atom 11; the dotted line between the carbon atoms 5 and 6 represents an optional double bond, such that when the double bond occurs, A and B independently represent -R10, halo, -OR11 -0C02R11 or -0C (0) R10, and when the double bond between the carbon atoms 5 and 6 is not present, A and B each independently represent (H, H), (-0R11, -OR11), (H, halo), (halo, halo), (alkyl) , H), (alkyl, alkyl), (H, -0C (0) R10), (H, -OR10), = 0, (aryl, F. represents: III - 1. i I IM I! \ I 2"(2) - •: H2C (O) N (R10) 2; (.- •) -S02-alkyl, -S02-driÍG, -S? 2? Iraiqu? Io, -50 -i¡e¡eíí) , i) i) - SG-iiie iiei iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii; Jo p¡¡ r Y • P r mu¡: NR13 II «ii uupdfc: Ü« at: Itt ji? Iici d 'i yiuuu que cunüs: Lti t: H, CN, - 302-alkyl (e.g., -S0 CH3), -C. { 0) -aril (for example, -C (0) (Vnt5, ** s say, -C (0) phenyl), -S02NR? NR14 (for example, -S02NH2), -C0) NR10R14 (for example, -C (0) NH2) and -OR10 (for example, OH and -0CH3); R1 is Aryo and R14 is selected Ndepeiu.i Leni. epieryl of the group consisting of H, dialkyl, aryl, and aralkyl; [61 u ,? gru or iini dipi? ue the fornorm: NR13 C. / NR10R15 wherein R ± w and Ri were previously defined; RI is alkyl, aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, or heterocyanoalkyl; (7) an l-amino-2-nitroethylene derivative of the formula: CH 02 p Cs SNHR 0: (8) -C (0) R, wherein R is alkyl, aralkyl heteroaryl; 9) -C (0) -0-R 16 po; Wherein R is selected from the group consisting of H, alkyl, aralkyl, (e.g., benzyl) and heteroaralkyl (for example, -CH2-imidazolyl); R 18 and R 1 each are independently selected from the group consisting of: 20 20 H; -C (0) 0R, wherein R represents alkyl, aralkyl, and heteroaralkyl; -S02R21 wherein R 1 is selected from the group consisting of alkyl (eg, Ci-Cß alkyl / as methyl), aryl, aralkyl, heteroaryl and heteroaralkyl; - 21 C (0) R; C? _6 alkaryl alkyl; and C3-6 cycloalkyl; and R is 0, 1 or 2; (11) alkyl, aryl, aralkyl, cycloalkyl; heterocycloalkyl or heteroaryl; (12) -SO2NR10R14; (13) -P (O) (R10) 2; (14) a sugar group of the formula: t > 2 6 wherein R * "" and R are independently selected from the group consisting of H, alkyl (Ci-Cß), aryl and aryl alkyl (Ci-Ce); and R2, R, R and R are independently selected from the group consisting of H, alkyl (C? e) f arylalkyl (C? -C6), and -C (O) alkyl (C? -C6) and -C? (O) aryl; or (15) -CH2C (0) OR, wherein R is selected from the group consisting of H, alkyl (e.g., -C (CH3) 3) aryl and heteroaryl; the compounds of this invention: (i) potentially inhibit farnesyl transferase protein, but not the geranylgeranyl transferase I protein, in vitro; (ii) block phenotypic change induced by a form of transforming Ras that is a farnesyl acceptor (but not by a transforming Ras form designed to be a geranylgenaryl acceptor; (iii) blocks the intracellular processing of Ras which is an acceptor of farnesil but not of Ras designed to be a geranylgeranil acceptor, and (iv) block the growth of abnormal cells in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl transferase protein and farnesylation of the Ras oncogenic protein. Thus, this invention further provides a method of inhibiting farnesyl transferase protein, (eg, ras farnesyl transferase protein) in mammals, especially humans, by administering an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl transferase protein, is useful in the treatment of the cancers described below. This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal cell growth refers to cell growth independently of normal regulatory mechanisms (eg, loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that express an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which the activation of aberrant Ras occurs.
This invention also provides a method for inhibiting or treating the growth of tumors by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the development of tumors expressing an activated Ras oncogene by administering an effective amount of the compounds described above. Examples of tumors that can be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as can be, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (e.g., acute myelogenous leukemia (AML)), cancer follicular thyroid, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma. It is considered that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, in which Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes - that is, the Ras gene itself is not activated by mutation to an oncogenic form - carrying out the inhibition or treatment by administering an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of oncogenic tyrosine kinase (eg, neu, src, abl, Ick, and fyn), can be inhibited or treated by tricyclic compounds described herein. The tricyclic compounds useful in the methods of this invention inhibit or treat abnormal cell growth. Without the desire to stick to the theory, it is considered that these compounds can function through the inhibition of the function of protein G, such as ras p21, by blocking the isoprenylation of protein G, making them this way they are useful in the treatment of proliferative disorders such as tumor growth and cancer. Without wishing to be bound by theory, these compounds are considered to inhibit Ras farnesyl transferase protein, and thus show antiproliferative activity against Ras transformed cells.
DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless stated otherwise: M + represents the molecular ion of the molecule in the mass spectrum; MH + represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Benzotriazol-1-yloxy represents L-methyl-tetrazole-5-lithium represents N-NN "CH3.alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino) represents straight and branched carbon chains and contains from 1 to 20 carbon atoms, preferably 1 up to 6 carbon atoms, alkenyl represents straight and branched carbon chains having at least one carbon-to-carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and more preferably from 3 carbon atoms. up to 6 carbon atoms, alkynyl represents straight and branched carbon chains containing at least one triple carbon to carbon bond and containing from 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, aralkyl represents an aryl group, as defined below, attached to an alkyl group, as defined above, wherein preferably the alkyl group is -CH2-, (e.g., phenyl); the aryl represents a group or carbocyclic containing from 6 to 15 carbon atoms and having at least one aromatic ring (for example, aryl is a phenyl ring), all available substitutable carbon atoms of the carbocyclic group being proposed as possible points of attachment, the optionally substituted carbocyclic group (eg, 1 to 3) with one or more halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, -COOR12 or -N0; cycloalkyl represents branched or unbranched saturated carbocyclic rings of 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; halo represents fluorine, chlorine, bromine and iodine; heteroaryl represents cyclic groups, optionally substituted with R 3 and R 4, having at least one heteroatom selected from 0, S, or N, the heteroatom interrupting a carbocyclic ring structure and with a sufficient number of delocalized pi electrons to provide the aromatic character , with aromatic heterocyclic groups preferably having a content of 2 to 14 carbon atoms, for example (1) thienyl (eg, 2- or 3-thienyl), (2; imidazolyl (eg, (2-4) - or 5-) imidazolyl), (3) triazolyl (for example, 3- or 5- [1,2,4-triazolyl]), (4) tetrazolyl, (5) substituted tetrazolyl, wherein R-27 represents aryl (e.g., phenyl), alkyl (e.g., -CH3) or aryl (eg, benzyl), (6) furyl (e.g., 2- or 3-furyl), (7) thiazolyl (or thiazyl), (8) pyrimidyl, (9) pyrazinyl (e.g., 2-pyrazinyl), (10) pyridazinyl (e.g., 3- or 4-pyridazinyl, (11) triazinyl (12) thiadiazolyl], (13) 2-, 3-, 4-, 5-, 6-, or 7-benzofuranyl), (14) 7-benzoxazolyl) (for example 2-, 4-, 5-, 6- or 7-benzoxazolyl), ( 15) indolyl (benzopyrrolyl) (for example, 2-, 3-, 4-, 5-, 6- or 7- indolyl), (16) pyrazolyl (for example, 3-, 4- or 5-pyrazolyl), ( 17) oxazolyl (for example, 2-, 4- or 5-oxazolyl), (18) 2-, 3- or 4-pyridyl or pyridyl N-oxide 3 (optionally substituted with R and R), wherein the Pyridyl N-oxide can be represented as: 19) isoxazolyl, (20) benzizoxazolyl, (21) pyrrolyl, (22) benzimidazolyl, (23) isoquinolinyl, (24) quinolinyl, (25) pyridopyrazinyl, (26) pyranyl, (27) benzothienyl, (28) isobenzofuranyl or ( 29) isothiazolyl; heteroarylalkyl (heteroaralkyl) represents a heteroaryl group, as defined, attached to an alkyl group as defined, preferably the alkyl group is -CH 2 -, for example, -CH 2 - (4- or 5-) imidazolyl; heterocycloalkyl represents a saturated, branched or unbranched carbocyclic ring containing from 3 to 15 carbon atoms; preferably from 4 to 6 carbon atoms, whose carbocyclic ring is interrupted by 1 to 3 hetero groups selected from -0-, -S-, -NR- (wherein R is as defined); suitable heterocycloalkyl groups include: (1) tetrahydrofuranyl (for example 2- or 3-tetrahydrofuranyl), (2) tetrahydrothienyl, for example, (2- or 3-tetrahydrothienyl), (3) piperidinyl (e.g., 2-3- or 4-piperidinyl), (4) pyrrolidinyl (e.g., 2- or 3-pyrrodinyl), (5) 2- or 3-piperizinyl, (6) 2-6 4-dioxanyl, (7) tetrahydropyranyl and (8) morpholinyl. The following solvents and reagents are referred to herein by the indicated abbreviations: ethanol (EtOH); ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); trifluoroacetic acid (TFA); N-methylmorpholine (NMM); 1- hydroxybenzotriazole (HOBT); triethylamine (Et3N); and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC). The reference to the position of the substituents R, R, R and R is based on the numbered structure of the rings: Preferably, the compounds of the formula 1.0 are represented by the compounds of the formula 1.1: wherein the substituents are as defined for formula 1.0. The compounds of formula 1.0 include compounds wherein R 2 and R 4 are H, and R 1 and R 3 are halo (preferably independently selected from Br or Cl). For example, R1 3 is Br and R is Cl. These compounds include the compounds wherein R is in the 3-position and R is in the 8-position, eg, 3-Br and 8-Cl. The compounds of formula 1.0 also include compounds wherein R 2 is H, and R 1, R 3 and R 4 are halo (preferably independently selected from Br or Cl).
Preferably, R 2 is H, and R 1, R 3 and R 4 are halo; a is N and b, c and d are carbons; A and B are each H2; the optional ligature between C5 and C6 is absent; X is CH; and R 5, R6, R7 and R 8 are H. Most preferably, R 1, R 3 and R 4 are independently selected from Br or Cl. Still more preferably, R2 is H, R1 is Br and R3 and R4 are independently selected from Cl and Br. More preferably, the compounds of formula 1.0 are represented by the compounds of formula 1.2 and formula 1.3: wherein R 1, R 3 and R 4 are each independently selected from halo, preferably Br or Cl; and A, B, X and W are as defined for formula 1.0. Most preferably, A and B are each H2; the optional ligature between C5 and C6 is absent; and X is CH. Most preferably, R 1 is Br; R3 and R4 are independently Br or Cl, and still more preferably R3 is Cl and R4 is Cl or Br; A and B are each H2; the optional link between C5 and C6 is absent; and X is CH. In the definition of R, in general, a preferred definition of aryl is phenyl, a preferred definition of aralkyl is benzyl and the preferred heteroaryl and heterocycloalkyl groups are as exemplified above.
Examples of the substituents -C (0) NR R are those wherein R and R are H or alkyl. Examples of the substituents -CH2C (O) NR10R11 are those wherein R and R are H or alkyl. Examples of the imidates for the substituent R include the groups wherein R is: (1) CN; (2) H; (3) - S02NR R wherein R and R are selected from the group consisting of: H and alkyl (e.g., methyl); (4) C (0) NR R wherein R and R are selected from the group consisting of: h and alkyl (e.g., methyl); (5) -S02- alkyl; or (6) -C (O) -aryl. Examples of the imidates also include groups wherein R 12 is phenyl. For example, the imidates for the substituent R include the groups wherein R 13 is selected from the group consisting of: CN, -C (0) NH 2, H, -S02NH2 / -S02NHCH3, -S02N (CH3) 2, -C (0) NHCH3, -S02CH3 and -C (0) C6H5. Examples of the imidates also include the groups wherein R is phenyl and R13 is selected from the group consisting of: CN, -C (0) NH2, H, -S02NH2, -S02NHCH3, -S02N (CH3) 2, -C (0) NHCH3, -S02CH3 and -C (0) C6H5.
Examples of the imidamido groups for the R substituent include the groups wherein R is selected from the group consisting of: (1) CN; (2) H; (3) -OR10; (4) - S02NR R wherein R and R are independently selected from the group consisting of: H and alkyl (eg, methyl), (5) -C (O) NR 10 R 14 wherein R 10 and R 14 are independently selected from the group consisting of: H and alkyl (for example, methyl); (6) -S02-alkyl; and (7) -C (0) -aryl.
Examples of the imidamido groups also include the groups in which R and R shown in the i idate structure (ie, not the R and R that are part of R) are selected from the group consisting of H and alkyl (e.g., -CH3), and wherein R 14 is H or heteroaralkyl (e.g., 3-pyridylmethyl) . For example, the imidamido groups for the R substituent include the groups in which R is selected from the group consisting of: CN, H, -0CH3, -0H, S02NH2, -S02NHCH3 -S02N (CH3) 2, -C (0) NHCH3, -S02CH3 and -C (0) C6H5. Examples of the imidamido groups also include the groups wherein R1 and R14 are selected from the group consisting of: H and (ie, 3-pyridylmethyl). Examples of the imidamido substituents further include the groups wherein: R and R are selected from the group consisting of H and 3-pyridylmethyl; and R13 is selected from the group consisting of: CN, H, -OCH3, -OH, S02NH2, -S02NHCH3, -S02N (CH3) 2, -C (0) NHCH3, -S02CH3 and -C (0) C6H5. In addition, examples of the imidamido substituents further include the groups wherein: (1) R and R are H, and R 14 is 3-pyridylmethyl; and (2) R10 and R14 are H, and R13 is selected from the group consisting of: CN, H, -0CH3, -0H, S02NH2, -S02NHCH3, -S02N (CH3) 2 -C (0) NHCH3 / -S02CH3 and -C (0) C6H5. Examples of the l-amino-2-nitroethylene derivatives for the substituent R include the groups wherein R 1 is alkyl, for example, methyl. 16 When R is -COR, R is preferably alkyl, for example, methyl, or aralkyl, for example, benzyl; examples of the heteroaryl groups R are pyridyl, indolyl, pyrrolyl, and N-substituted pyrrolyl (for example, N-alkylpyrrolyl, such as N-alkylpyrrolyl-rw / 1 to v or v.? -rii? -? it ~ r * r ^ * - ^ - i? i < 11 n > "1 £ 2. O - (0) 0R, R * is preferably alkyl, for example, methyl, or araiquno, for example, O H? 1B II I ~ C-C- (CH2) r-r Cusndo P is R17 R and r is 0, R "1" 'preferably H, alkyl, aralkyl or heteroaralkyl, and R 18 and R 19 are preferably H, -C (0) 0R20, 1 O where R "is alkyl, -S02R, 2" "11 'wherein R, 2i1J" is alkyl, -C ^ R * "1, where ^ is alkyl or aryl, when r is io 2, R of preferred is H and R and R are preferably alkyl, When R is -S02NR10R14, R10 and R14 are preferably H or alkyl When R is -P (0) (R10) 2 R10 is preferably alkyl When R is a sugar, preferably has the formula: wherein R, 2"3, R, 2" 4, R25 and R26 are -C (O) alkyl, especially aceLilo. The preferred R groups are -C (0) N (R, i1U0), 2, CH2C (0) N (R) wherein R, 10 is preferably H, and -S0 -alkyl, preferably -SO2CH3.
The compounds of asrorias i 3 4 are preferred when X is CH or N, and R, R and R are halo. The preferred compounds of this invention are represented by the compounds of the formulas: wherein R 1, R 3 and R 4 are halo and the remaining substituents are as already defined, with the compounds of formula 1.5A being most preferred. Those drawn on the ring systems indicate that the indicated bond may be attached to any of the carbon atoms of the ring substituibies. Certain compounds of the invention can exist in different isomeric forms (e.g., enantiomers and in pure form and in mixture, including racemic mixtures) Also included are oxalic esters Certain tricyclic compounds will be acidic in nature, for example those compounds which They have a carboxyl or phenolic hydroxyl group These compounds can form acceptable anamaceuticals Examples of these salts may include sodium, potassium, calcium, aluminum salts, JGO piaca, and salts formed with the pharmaceutically acceptable amines are contemplated. such as ammonia, alkylamines, hydroxyaikyanoins, N-methygiucamine and the like Certain basic tricyclic compounds also form pharmaceutically acceptable salts, for example, acid addition salts, for example, the nitrogen atoms of the pyrido portion can form salts with strong acids, whereas compounds that have basic substituents such as amino groups also form salts with weaker acids. Examples of the acids suitable for the formation of the salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methansulic, and other mineral and carboxylic acids. well known to those skilled in the art. The salts are prepared by contacting the free base form with - >; - > a sufficient quantity of the desired acid to produce a sai in the conventional manner. The free base forms can be regenerated by treating the sai with a dilute aqueous solution of the suitable base such as dilute aqueous NaOH, potassium carbonate, ammonia, and sodium bicarbonate. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the acidic and basic salts are otherwise equivalent to their respective free base forms for the purposes of the invention. All of these acidic and basic salts are proposed to be pharmaceutically acceptable salts within the scope of the invention and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The compounds of the invention can be prepared according to the methods described in WO 95/10516 published April 20, 1995, the co-pending application series 08 / 410,187 filed on March 24, 1995, the co-pending application No. 08 series. / 577,951 filed December 22, 1995, and copending application series No. 08 / 615,760 filed March 13, 1996, the descriptions of each are incorporated herein by reference; and in accordance with the procedures described below.
Can they be prepared by rearming? ? r, < ..or £:? \ e;: ~ > For the formula: Where tcdce substituents are as defined in formula 1.0, with 1-Nt-butoxycarbonylpyrrolidinyl acetic acid or standard coupling conditions, for example, at room temperature in a solvent such as DMF and in the presence of coupling agents such as DEC, HOBT , and N-methylmorpholine, to produce a compound of the formula: or by reacting a compound of formula 19.0 with N-boc-homoprolin methyl ester under standard coupling conditions, for example, at room temperature in a co-solvent or DMF and in the presence of coupling agents such as DEC, HOBT N-methylmorroline, to produce a good-looking c .a formula: A compound of formula 20.0 or 20.1 then is reacted with TFA then NaOH to produce a compound of formula 2.1.0 or 21.1, respectively: The 1-N-t-butoxycarbonylpyrrolidinyl acetic acid is prepared according to the process described in J.
Med. Chem. 33 (1990), p. 71-77, by the reaction of homo-ß-proline with di-tert-butyl bicarbonate at pH 9. The use of (R) - (-) - or (S) - (+) - homo-ß-proline produces the corresponding compound (R) -? -) - or (S) - (+) - homopho-t-butoxy which a your time? will produce the compound [R) -. { -) - or ÍS) -I +) corresponding to the formula. 1.0. The N-boc-homoproline, prepared according to the procedure described in Helvita Che ica Acta, 59, (1761, p 1918, produces the (S) -isomer of the compound of the formula 21.1. The compounds of the formula 19.0 they can be prepared according to the procedures described in WO 95/10516 published on April 20, 1995 and serial applications No. 08 / 577,951 filed on December 22, 1995, and series No. 08 / 615,760 filed on December 13, 1995. March 1996, the descriptions of which have already been incorporated herein by reference to them. example, the preparation of the compounds: described in preparation example 8, example 18 and preparation examples 4, 6, 7, 9, and 10, respectively, of the serial application No. 08 / 615,760. These intermediates, representative of the compounds of formula 19.0, can be reacted with 1-N-t-butoxycaroonyl-pyrrolidinium acetic acid or N-boc-homoproline to prepare the compounds of the respective formulas 21.0. The compounds of the formula (19.01 are also prepared as described in US 5,151,423 and in accordance with the methods described below. (19.0) wherein the position ü-3 of the pyridine ring in the L-cyclic structure is replaced by bromine and R 3 and R 4 are independently selected from hydrogen and halo, can also be prepared by a process consisting of the following steps: (a) ) the reaction of an amide of the formula: wherein R a is Br, R a is hydrogen and R a is Cg-Cß alkyl, aryl or heteroaryl; R a is C 1 -C 7 alkyl, aryl or heteroaryl; R is hydrogen; R a and R a are independently selected from the group consisting of C 1 -C 6 alkyl, aryl; R and R a, together with the nitrogen to which they are attached, form a ring containing 4 to 6 carbon atoms or having 3 to 5 carbon atoms and a hetero portion selected from the group consisting of -O- and -NR a- wherein R a is H, Cß-Cß alkyl, or phenyl; with a compound of the formula: wherein R a, R a, R a and R a are independently selected from the group consisting of hydrogen and halo, and R d is Cl or Br, in the presence of a strong base to obtain a compound of the formula: (b) the reaction of a compound of step (a) with (i) POCI3 to obtain a cyano compound of the formula (ii) DIBALH to obtain an aldehyde of the formula (c) the reaction of the cyano compound or the aldehyde with a piperidine derivative of the formula: LMg Y-wherein L is a leaving group selected from the group consisting of Cl or Br, to obtain a ketone or an alcohol of the following formula, respectively: (d)) cyclization of the ketone with CF3SO3H to obtain a compound of the formula (19.0) wherein the dotted line represents a double bond; or (d) (ii) the cyclization of the alcohol with polyphosphotic acid to obtain a compound of the formula (19.0) wherein the dotted line represents a single bond. The methods for the preparation of the compounds of the formula (19.0) are described in WO 95/10516, US 5,151,423 and the use of a tricyclic ketone intermediate is described below. These intermediaries of the formula: wherein H1, R1, R1, iYa, and R are independently selected from the group consisting of hydrogen and halo, can be prepared by the following process consisting of: (a) the reaction of a compound of the formula: (i) with an amine of the formula NHR aR a, where R a and R f A are as defined in the previous process; in the presence of a palladium and carbon monoxide catalyst to obtain an amide of the formula: (ii) with an alcohol of the formula R a 0H, wherein R 10a is C 1 -C 6 lower alkyl or C 3 -C 6 cycloalkyl, in the presence of a palladium and carbon monoxide catalyst to obtain the ester of the formula: Followed by the reaction of the ester with an amide of the formula NHR R to obtain the amide; (b) the reaction of the amide with a benzyl compound substituted with iodine of the formula: wherein R a, R * "a, R a, R a and R 'a are as defined above, in the presence of a strong base to obtain a compound of the formula: (c) the cyclization of a compound of step (b) with a g-reactive of the formula R ^ IgL, wherein R is C 1 -C 12 alkyl, aryl or heteroaryl and L is Br or Cl, provided that when before cyclization, the compounds wherein R or R is hydrogen are reacted with an appropriate N-protecting group. The (+) isomers of the compounds of the formula (19.0) wherein X is C and the double bond is present can be prepared with high enantioselectivity using a process consisting of above catalysed transesterification. Preferably, a racemic compound of the formula (19.0), wherein X is C and the double bond is present, is reacted with an enzyme, such as Toyobo LIP-300 and an acylating agent such as trifluoroethyl isobutyrate.; the resulting amide (+) is then hydrolysed, for example by refluxing with an acid such as H2SO4, to obtain the corresponding optically enriched (+) isomer. The double bond can then be reduced by methods well known in the art, for example, using DIBAL. Otherwise, a racemic compound of the formula (19.0) wherein X is CH and the double bond is not present, can be prepared first by reducing a compound of the formula (19.0) wherein X is C and the double bond is present, to the corresponding racemic compound of formula (19.0) wherein X is CH and then treating with the enzyme (Toyobo LIP-300) and the acylating agent as already described to obtain the (+) - amide, which is hydrolyzed to obtain the optically enriched (+) isomer. In the preferred enzymatic process, the C-10 substituent is not hydrogen. The compounds of the formula (1.0) consisting of a pyridyl N-oxide in the tricyclic portion of the molecule can be prepared by methods well known in the art. For example, the compound of the formula (19.0) can be reacted with MCPBA in a suitable organic solvent, for example, CH2C12 (usually anhydrous), at a suitable temperature, to obtain an N-oxide of the formula (19.1) .
H (19.1) In general, the solution of the organic solvent of the formula (19.0) is cooled to about 0 ° C before adding MCPBA. The reaction is then allowed to warm to room temperature during the reaction period. The desired product can be recovered by the standard separation means, for example, the reaction mixture can be washed with an aqueous solution of a suitable base, for example, NaHC? 3 or saturated NaOH (for example, NaOH IN, and then dried on anhydrous MgSO 4 The solution containing the product can be concentrated under vacuum, and the product can be purified by standard means, for example, by chromatography using silica gel (for example, flash column chromatography). In formula 1.0, the compounds of formula 21 are reacted with suitable reagents to join the different R groups as exemplified below. Those skilled in the art will appreciate that the methods of preparing the compounds of formula 1.0 are not limited to the following examples, but other methods known in the art may be applied.The following are common examples of the preparation of the s different starting materials, including (R) - (-) and (S) - (+) l-N-t-butoxycarbonylpyrrodinil-3-acetic acid and the compounds of formula I.
PREPARATION EXAMPLE 1 (R) - (-) l-N-t-Butoxycarbonylpyrrolidinyl-3-acetic Sus 3.8 g (29.43 mmol) of (R) -homo-b-proline 1 in 75 ml of CH30H-H20 (1: 1). Adjust the pH with NaOH IN. Add 7.06 g (32.34 mmol) of di-tert-butyl dicarbonate slowly (25 min) while maintaining pH 9 and stir the mixture at room temperature overnight. Concentrate the mixture in vacuo to a residue, then partition the residue between 100 ml of CH2C12 and 100 ml of 10% citric acid (aqueous). Dry the organic phase over MgSO4 and concentrate in vacuo to give 2.1 g of compound 3, mp = 100 ° C; mass spectroscopy: MH + = 230.
EXAMPLE OF PREPARATION 2 (S) - (+) l-t-Butoxycarbonylpyrrolidinyl-3-acetic [sic] React 1.9 g (1.47 mmol) of (S) -homo-b-proline 2 with 3.53 g (1.61 mmol) of di-tert-butyl dicarbonate using substantially the same procedure as described above to give 2.8 g of compound 4 , pf = 102 ° C; MH + = 230; XH NMR (CDC13, 200 MHz): 3.2-3.7 (m, 3H); 2.9 (m, 1H); 2.4-2.6 (m, 3H); 2.1 (m, 2H); 1.55 (m, 1H); 1.4 (s, 9H).
EXAMPLE OF PREPARATION 3 Combine 14.95 g (39 mmol) of 8-chloro-l 1 - (1-ethoxy? -carbonyl-4-piperidinyl) -HH-benzo- [5,6] cyclohepta [1,2-b] pyridine and 150 ml of CH2CI2, then add 13.07 g (42.9 mmol) of (nBu) 4NN03 and cool the mixture to 0 ° C. Slowly add (drop by drop) a 6.09 ml solution (42.9 mmol) of TFAA in 20 ml of CH2C12 for 1.5 hours. Keep the mixture at 0 ° C overnight, then wash successively with saturated NaOH3 (aqueous), water and brine. Dry the organic solution over Na2SO4, concentrate in vacuo to a residue and chromatograph the residue (silica gel, gradient EtOAc / hexane) to obtain 4.32 g and 1.90 g of two product compounds 3A (i) and 3A (ii), respectively . Mass spectroscopy for compound 3A (i): MH = 428.2; Mass spectroscopy for compound 3A (ii): MH = 428.3.
Step B Combine 22.0 g (51.4 mmol) of product 3A (i) from step A, 150 ml of 85% EtOH (aqueous), 25.85 g (0.463 mol) of Fe powder and 2.42 g (21.8 mmol) of CaCl2, and heat reflux overnight. Add 12.4 g (0.222 mol) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2 hours. Add another 12.4 g (0.222 mol) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2 more hours. Filter the hot mixture through Celite®, wash the Ceiite® with 50 ml of hot EtOH and concentrate the filtrate in vacuo to a residue. Add 100 ml of anhydrous EtOH, concentrate to a residue and chromatograph the residue (silica gel, MeOH / CH2CY gradient) to obtain 16.47 g of the product compound.
Ras: Combine 16.47 g (41.4 mmol) of the product of step B, and 1 0 IIIJ of HBr di 48? -, (donoso) and cool -'i ° C. Add to it (drop by drop) 18 ml of bromine, then slowly add to it (gol d got,? nrid solution of o.55 g (u.1 4 mol) of NaN02 in 85 ml of water. Stir for 45 minutes at -3 ° to 0 ° C, then dj.sldr d pK igijdl 10, -dioi oridiiuo H OH di 0 * (aqueous), extract with EtOAc, wash the extracts with brine and extract the HXi.idY on NA2Hü-? ncern 1di sLd a residue and perform i (qvl of silica, gradient F.rúAC / hexa or • pa to 00teno 1 .6 g and ~ -, .2, -, g Y- ds composed of R? duct P (i) and 3C (ii), specify L.
Spectrosccpi .ra el -omr-uecr.- "? C (ii i MH '-53 Hi uro i i ar e? prouucLo .e (i) ae i aso C uisoivjenuo in Concentrate HCl and heat at approximately 100 ° C for 16 hours. Repeat me / .oi d, peni r a 1 i d r with NdOH 1H (donoso).
Extract with CH2C12, dry the extracts over MgSO4, filter and copolymerize the LiLul compound. Mass spectroscopy: MH = 466.9 EXAMPLE OF PREPARATION 4 ? .. ot! [) i li r o. nr > g [nn.i Mimo 'i ce ei i i e; -! e 'oe i doiao < «- (8-Chloro-3-bromo-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2- H 2 SO 4 concentrated n -5 ° C, then add 4.8 g { 56.4 mpi? Li The mixture is filtered and washed with concentrated NH4OH (aqueous), filtered, washed with 300 ml of water, then extracted with 500 ml of CH2C1. Extract with 200 ml of water, dry over MgSO4, then filter and concentrate in vacuo to a residue, chromatograph the residue (silica gel, EtOAC 10% / CH2C12) to obtain 24.4 g (86% yield) of the product pf = 165-167 ° C, mass spectroscopy: MH = 506.508 (Cl) Elemental analysis: calculated -C, 52.13; H, 4.17; N, 8.29 found -C, 52.18; H, 4.51; N, 8.16 Step B; Combine 20 q (40.5 mmol) of the product dt, l step A and 200 ml of concentrated HSo4 at 20 ° C, then cool the mixture to 0 ° C. Add 7.12 g (24.89 mmol) of 1,3-dibromo-5,5-dimethylhydantoin to the mixture and stir for 3 hours at 20 ° C. Cool to 0 ° C, add an additional 1.0 g (3.5 mmoii of dibromo hydantoin and stir at 20 ° C for 2 hours.) Pour the mixture into 400 g of ice, basify with concentrated NH4OH (aqueous) at 0 ° C, and collect the Resulting solid by filtration Wash the solid with 300 ml of water, mix in 200 ml of acetone and filter to give 19.79 g (85.6% yield) of the product, mp = 236-237 ° C, mass spectroscopy: MH + = 586 (Cl) Elemental analysis: calculated -C, 45.11, H, 3.44, N, 7.17 found -C 44.95, H, 3.57, N, 7.16.
Step C: Combine 25 g (447 mmol) of Fe filings, 10 g (90 mmol) of CaCl and a suspension of 20 g (34.19 mmol) of the product of step B in 700 ml of EtOH / water 90:10 at 50 ° C.
Heat the mixture to reflux overnight, filter through Celite® and wash the filter cake with 2 X 200 ml of hot EtOH. Combine the filtrate and the washings and concentrate in vacuo until a residue is obtained. Extract the residue with 600 ml of CH2C12, wash with 300 ml of water and dry over MgSO4. Filter and concentrate in vacuo to a residue, then chromatograph (silica gel, 30% EtOAC / CH2Cl2) to obtain 11.4 g (yield 60%) of the product, m.p. = 211-212 ° C, mass spectroscopy: MH + = 556 (Cl). Elemental analysis: calculated -C, 47.55; H, 3.99; N, 7.56 found -C, 47.45; H, 4.31; N, 7.49 Step D: Slowly add (in portions) 20 g (35.9 mmol) of the product from step C to a solution of 8 g (116 mmol) of NaN02 in 120 ml of concentrated HCl (aqueous) at -10 ° C. Stir the resulting mixture at 0 ° C for 2 hours, then slowly add (dropwise) 150 ml (1.44 mol) of 50% H3P0 at 0 ° C for a period of 1 hour. Stir at 0 ° C for 3 hours, then pour 600 g of ice and basify with concentrated NH 4 OH (aqueous). Extract with 2 x 300 ml of CH2C1, dry the extracts over MgSO4, then filter and concentrate in vacuo to a residue. Perform chromatography of the residue (silica gel, 25% EtOAc / hexanes) to give 13.67 g (yield 70%) of the product, m.p. = 163-166 ° C, mass spectroscopy: MH + = 541 (Cl).
Elemental analysis: calculated -C, 48.97; H, 4.05; N, 5.22 found -C, 48.86; H, 3.91; N, 5.18 Step E: Combine 6.8 g (12.59 mmol) of the product from step D and 100 ml of concentrated HCl (aqueous) and stir at 85 ° C overnight. Cool the mixture, pour it into 300 g of ice and basify with concentrated NH4OH (aqueous). Extract with 2 x 300 ml of CHC12, then dry the extracts over MgSO4. Filter, concentrate in vacuo to a residue, then chromatograph (silica gel, 10% MeOH / EtOAc + NH 4 OH (aq.) 2%) to obtain 5.4 g (92% yield) of the title compound. p.f. = 172-174 ° C. mass spectroscopy: MH = 469 (FAB). Elemental analysis: calculated -C, 48.69; H, 3.65; N, 5.97 found -C, 48.83; H, 3.80; N, 5.97 EXAMPLE OF PREPARATION 5 Hydrolyze 2.42 g of 4- (8-chloro-3-bromo-5,6-dihydro-IIH-benzo [5,6] cyclohepta [1,2-b] pyridin-1-ylidene) ethyl ester. piperidine-l-carboxylic acid through practically the same procedure as that described in Preparation Example 3, step D, to give 1.39 g (yield 69%) of the product.
Step B: Combine 1 g (2.48 mmol) of the product of step A and 25 ml of dry toluene, add 2.5 ml of 1 M DIBAL in toluene and heat the mixture to reflux. After 0.5 hours, add another 2.5 ml of 1 M DIBAL in toluene and heat at reflux for 1 hour. (The reaction is monitored by TLC using 50% MeOH / CH2Cl2 + NH4OH (aqueous).) Cool the mixture to room temperature, add 50 mL of 1M HCl (aqueous) and stir for 5 min. Add 100 ml of IN NaOH (aqueous), then extract with EtOAc (3% 50 ml). Dry the extracts over MgSO4, filter and concentrate in vacuo to obtain 1.1 g of the title compound.
EXAMPLE OF PREPARATION 6 racemic, as well as the isomers (+) and (-) Combine 16.6 g (0.03 mol) of the product from preparation example 4, step B, with a 3: 1 solution of CH3CN and water (212.65 ml of CH3CN and 70.8 ml of water) and stir the resulting mixture overnight at room temperature. Add 32.833 g (0.153 mol) of NaI04 and then 0.31 g (2.30 mmol) of Ru02 and stir at room temperature to obtain 1.39 g (yield 69%) of the product. (The addition of RuO [sic] is accompanied by an exothermic reaction and the temperature rises ° to 30 ° C.) Shake the mixture for 1.3 hours. (The temperature returns to 25 ° C after approximately 30 min.), Then filter to remove the solids and wash the solids with CH2C12. Concentrate the filtrate in vacuo to obtain a residue and dissolve the residue in CH2C12. Filter to remove insoluble solids and wash solids with CH2C12. Wash the filtrate with water, concentrate to a volume of approximately 200 ml and wash with bleach, then with water. Extract 6N HCl (aqueous). Cool the aqueous extract to 0 ° C and slowly add 50% NaOH (aqueous) to adjust to pH = 4 while maintaining the temperature < 30 ° C. Extract twice with CHC12, dry over MgSO4 and concentrate in vacuo until a residue is obtained. Mix the residue in 20 ml of EtOH and cool to 0 ° C. Collect the resulting solids by filtration and dry the solids in vacuo to obtain 7.95 g of the product. PH NMR (CDCl 3, 200 MHz); 8.7 (s, 1H), 7.85 (m, 6H, 7.5 (d, 2H), 3.45 (, 2H), 3.15 (m, 2H).
Step B; Combine 21.58 g (53.75 mmol) of the product from step A and 500 ml of an anhydrous 1: 1 mixture of EtOH and toluene, add 1.43 g (37.8 mmol) of aBH4 and heat the mixture at reflux for 10 min. Cool the mixture to 0 ° C, add 100 ml of water, then adjust to pH = 4-5 with 1M HCl (aqueous) while maintaining the temperature at < 10 ° C. Add 250 ml of EtOAc and separate the layers. Wash the organic layer with brine (3 x 50 ml) then dry over Na 2 SO 4. Concentrate in vacuo to a residue (24.01 g) and chromatograph the residue (silica gel, 30% hexane / CH2Cl2) to obtain the product. The impure fractions were purified by reverse chromatography. A total of 18.57 g of the product was obtained. X H NMR (DMSO-d 6, 400 MHz): 8.5 (s, 1 H); 7.9 (s, 1H); 7.5 (d or d, 2H); 6.2 (s, 1H); 6.1 ís, 1H); 3.5 (m, 1H); 3.4 (m, 1H); 3.2 (m, 2H).
Combine 18.57 g (46.02 mmol) of the product from step B and 500 ml of CHCl3, then add 6.70 ml (91.2 mmol) of S0C12, and stir the mixture at room temperature for 4 hours. Add a solution of 35.6 s (0.413 mol) of piperazine in 800 ml of THF over a period of 5 min, and stir the mixture for 1 hour at room temperature. Heat the mixture at reflux overnight, then cool to room temperature and dilute the mixture with 1 l of CH2C12. Wash with water (5 x 200 ml), and extract the aqueous wash with CHCl3 (3 x 100 ml). Combine all organic solutions, wash with brine (3 x 200 ml) and dry over MgSO4. Concentrate in vacuo to a residue and chromatograph (silica gel, 5% gradient, 7.5%, 10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 18.49 g of the title compound as a racemic mixture.
Step D - separation of enantiomers: The racemic compound of the title of step C is separated by preparative chiral chromatography (Chiralpack AD, column 5 cm x 50 cm, flow rate 100 ml / min, 20% IPrOH / hexane + 0.2% diethylamine), to obtain 9.14 g of the isomer (+) and 9.30 g of the isomer (-). The physicochemical data for the (+) isomer: p.f. = 74.5 ° -77.5 ° C, mass spectroscopy: MH + = 471.9; [a] 25D = + 97.4 ° (8.48 mg / 2mL MeOH). Physicochemical data for the (-) isomer: p.f. = 82.9o-84.5 ° C, mass spectroscopy: MH + = 471.8; [α] 25D = + 97.4 ° (8.32 mg / 2mL MeOH).
EXAMPLE OF PREPARATION 7 Combine 15 g (38.5 mmol) of 4- (8-chloro-3-bromo-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridin-1-ylidene ethyl ether. ) -1-piperidine-l-carboxylic acid and 150 ml of concentrated H2S? 4 at -5 ° C, then add 3.89 g (38.5 mmol) of KNO3 and stir for 4 h. Empty the mixture in 3 1 of ice and basify with 50% NaOH (aqueous). Extract with CH2C12, dry over MgSO4, then filter and concentrate in vacuo to a residue. Recrystallize the acetone residue to give 6.69 g of the product. X H NMR (CDCl 3, 200 MHz): 8.5 (s, 1 H); 7.75 (s, 1H); 7.6 (s, 1H), 7.35 (s, 1H); 4.15 (q, 2H); 3. b '(, 2H,; 3.5-3.1 (m, 4H), 3.0-2.8 (, 2H), 2.6-2.2 (, 4H), 1.25 <t, 3h).
Step B: Combine 6.69 g (13.1 mmol) of the product from step A and 100 ml of 85% EtOH / water, add 0.66 g (5.9 mmol) of CaCl2 and 6.56 g (117.9 mmol) of Fe and heat the mixture to reflux overnight. Filter the hot reaction mixture through Celite® and wash the filter cake with EtOH. Concentrate the filtrate in vacuo to give 7.72 g of the product. Mass spectroscopy: MH = 478.0.
Step C: Combine 7.70 g of step B and 35 ml of HOAc, then add 45 ml of a Br2 solution in HOAc and stir the mixture at room temperature overnight. Add 300 ml of IN NaOH (aqueous), then 75 ml of 50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgSO4 and concentrate in vacuo to a residue. Perform chromatography of the residue (silica gel, 20% -30% EtOAc / hexane) to obtain 3.47 g of the product (together with another 1.28 g of partially purified product). Mass spectroscopy: MH = 555.9. XH NMR (CDC13, 300 MHz): 8.5 (s, 1H); 7.5 (s; 1H); 7.15 (s, 1H); 4.5 (s; 2H); 4.15 (m, 3H); 3.8 (br s, 2H); 3.4-3.1 (m, 4H); 9-2.75 (m, 1H); 2.7-2.5 (m, 2H); 2.4-2.2 (m, 2H); 1.25 (, 3H).
Step D: Combine 0.557 g (5.4 mmol) of t-butylnitrite and 3 ml of DMF, and heat the mixture to 60-70 ° C. Slowly add (dropwise) a mixture of 2.00 g (3.6 mmol) of the product from step C and 4 ml of DMF, then cool the mixture to room temperature. Add another 0.64 ml of t-butylnitrite at 40 ° C and reheat the mixture at 60-70 ° C for 0.5 hours. Cool to room temperature and pour the mixture into 150 ml of water. Extract with CH2C12, dry over MgS? and concentrate in vacuo until a residue is obtained. Perform chromatography of the residue (silica gel, 10% -20% EtOAc / hexane) to obtain 0.74 g of the product. Mass spectroscopy: MH + = 541.0. 1 H NMR (CDCl 3, 200 MHz): 8.52 (s, 1 H); 7.5 (d, 2H); 7.2 (s, 1H); 4.15 (q, 2h); 3.9-3.7 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.5 (m, 2H); 2.4-2.2 (m, 2H); 2.1-1.9 (m, 2H); 1.26 (t, 3H).
Step E: Combine 0.70 g (1.4 mmol) of the product from step D and 8 ml of concentrated HCl (aqueous) and heat the mixture to reflux overnight. Add 30 ml of 1 N NaOH (aqueous), then 5 ml of 50% NaOH (aqueous) and extract with CH2C12. Dry the extract over MgSO4 and concentrate in vacuo to give 0.59 g of the title compound. Mass spectroscopy: MH + = 468.7. p.f. = 123.9 ° -124.2 ° C.
EXAMPLE OF PREPARATION 8 [racemic, as well as the isomers (+) and (-)] Step A: Prepare a solution of 8.1 g of the title compound of Preparation Example 7 in toluene and add 17.3 ml of a 1M solution of DIBAL in toluene. Heat the mixture to reflux and slowly add (dropwise) another 21 ml of a 1 M DIBAL / toluene solution for a period of 40 min. Cool the reaction mixture to about 0 ° C and add 700 ml of HCl (aqueous). Separate and discard the organic phase. Wash the aqueous phase, with CH2C12, discard the extract, then basify the aqueous phase by adding 50% NaOH (aqueous). Extract with CHC12, dry the extract over MgSO4 and concentrate in vacuo to give 7.30 g of the title compound, which is a racemic mixture of enantiomers.
Step B - separation of enantiomers: The racemic compound of the title of step A is separated by preparative chiral chromatography (Chiralpack AD column, 5 cm x 50 cm, using IPrOH / 50% hexane + 0.2% diethylamine) to give the (+) isomer or the (-) isomer of the composed of the title. Physicochemical data for the (+) isomer: p.f. 148.8 ° C; mass spectroscopy: MH + = 469; [α] 25D = + 65.6 ° (mg / 2mL MeOH). Physicochemical data for the (-) isomer: p.f. = 112 ° C; mass spectroscopy: MH 469; [α] 25 = + 65.2 ° (mg / 2mL MeOH).
EXAMPLE OF PREPARATION 9 [racemic, as well as the isomers (+) and (-)] Combine 40.0 g (0.24 mol) of the initial ketone and 200 ml of H2S? 4 and cool to 0 ° C. Slowly add 13.78 g (0.136 mol) of KNO3 for a period of 1.5 hours, then warm to room temperature and stir overnight. Work the reaction using practically the same procedure as the one described for preparation example 4, step A. Perform chromatography (silica gel, 20%, 30%, 40%, 50% EtOAc / hexane, then 100% EtOAc %) to obtain 2 g of the 9-nitro product, together with a smaller amount of the 7-nitro product and 19.0 g of a mixture of 7-nitro and 9-nitro compounds.
Step B: React 28 g (76.2 mmol) of the 9-nitro product from step A, 400 ml of 85% EtOH / water, 3.8 g (34.3 mmol) of CaCl 2 and 38.28 g (0.685 mol) of Fe using practically the same procedure as that described for preparation example 4, step C to give 24 g of the product.
Step C: Combine 13 g (38.5 mmol) of the product from step B, 140 ml of HOAc and slowly add a 2.95 ml solution. (57.8 mmol) of Br2 in 10 ml of HOAc for a period of 20 minutes. Stir the reaction mixture at room temperature, then concentrate in vacuo to a residue. Add CH2C12 and water, then adjust to pH equal to 8-9 with 50% NaOH (aqueous). Wash the organic phase with water, then brine and dry over Na2SO4. Concentrate in vacuo to give 11.3 g of the product.
Step D: Cool 100 ml of concentrated HCl (aqueous) at 0 ° C, then add 5.61 g (81.4 mmol) of NaN02 and stir for 10 minutes. Slowly add (in portions) 11.3 g (27.1 mmol) of the product from step C and stir the mixture at 0-3 ° C for 2.25 hours. Slowly add (dropwise) 180 ml of 50% H3P02 (aqueous) and allow the mixture to stand at 0 ° C overnight. Slowly add (dropwise) 150 ml of 50% NaOH for 30 minutes, adjust to pH = 9, then extract with CH2C12. Wash the extract with water, then brine and dry over Na2SO4. Concentrate in vacuo to a residue and chromatograph (silica gel, 2% EtOAc / CH2Cl2) to obtain 8.6 g of the product.
Step E: Combine 8.6 g (21.4 mmol) of the product from step D and 300 ml of MeOH and cool to 0-2 ° C. Add 1.21 g (32.1 mmol) of NaBH4 and stir at ~ 0 ° C for 1 hour. Add another 0.121 g (3.21 mmol) of NaBH4, stir for 2 hours at 0 ° C, then let stand overnight at 0 ° C. Concentrate in vacuo to a residue, then partition the residue between CH2C12 and water. Separate the organic phase and concentrate in vacuo (50 ° C) to give 8.2 g of the product.
Step F: Combine 8.2 g (20.3 mmol) of the product from step E and 160 ml of CH2C12, cool to 0 ° C, then slowly add (dropwise) 14.8 ml (203 mmol) of S0C12 over a period of 30 minutes. Heat the mixture to room temperature and stir for 4.5 hours, then concentrate in vacuo to a residue, add CHCl and wash with 1N NaOH (aqueous) then brine and dry over a2SO. Concentrate in vacuo to a residue, then add dry THF and 8.7 g (101 mmol) of piperazine and stir at room temperature overnight. Concentrate in vacuo to a residue, add CH2C12 and wash with 0.25 N NaOH (aqueous), water and then brine. Dry over Na S04 and concentrate in vacuo to obtain 9.46 g of the crude product. Perform chromatography (silica gel, 5% MeOH / CH2Cl2 + NH3) to obtain 3.59 g of the title compound, as a racemate. H NMR (CDCl 3, 200 MHz): 8.43 (d, 1H); 7.55 (d, 1H); 7.45 (d, 1H); 7.11 (d, 1H); 5.31 (s, 1H); 4.86-4.65 (m, 1H); 3.57-3.40 (m, 1H); 2.98-2.55 (m, 6H); 2.45-2.20 (m, 5H).
Step G - Separation of enantiomers The racemic compound of the title of step F (5.7 g) is subjected to chromatography as described for preparative example 6, step B using 30% IPrOH / hexane + 0.2% diethylamine, to give 2.88 g of the R- (+) isomer and 2.77 g of the S ~ isomer (Y of the title compound) Physico-aqueous data of the isomer (R) - (+) mass spectroscopy MH = 470; = + 12.1 ° 10.9 mg / 2mL MeOH). Physicochemical data for the S - (-) isomers: mass spectroscopy: MH + = 470; [a] 25D - -13.2 ° (11.51 mg / 2mL MeOH).
EXAMPLE OF PREPARATION 10 [racemic, as well as the isomers (+) and (-)] Step A: Combine 13 g (33.3 mmol) of the title compound of Preparation Example 4, Step D, and 300 mL of toluene at 20 ° C, then add 32.5 mL (32.5 mmol) of a 1 M solution of DIBAL in toluene. Heat the mixture at reflux for 1 hour, cool to 20 ° C and add 32.5 ml of a solution 1 of DIBAL in toluene. Heat the mixture at reflux for 1 hour. Cool the mixture to 20 ° C and empty it on a mixture of 400 g of ice, 500 ml of EtOAc and 300 ml of 10% NaOH (aqueous). Extract the organic layer with CH2C12 (3 x 200 ml), dry the organic layers over MgSO0 then concentrate in vacuo to a residue. Perform chromatography (silica gel, 12% MeOH / CH2Cl2 + 4% NHOH) to give 10.4 g of the title compound as a racemate. Mass spectroscopy: MH + = 469 (FAB). partial XH NMR (DCDI3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.06 (d, 1H); 3.95 (d, 1H).
Step B - Separation of enantiomers: The racemic compound of the title from step A is separated by preparative chiral chromatography (Chiraipack AD column, 5 cm x 50 cm, using 5% IPrOH / hexane + 0.2% diethylamine), to give the (+) isomer and the (-) isomer of the title compound. Physicochemical data for the (+) isomer: mass spectroscopy: MH + = 470.9 (FAB); [α] 25 D = + 43.5 ° (c = 0.402, EtOH); partial XH NMR (CDC13, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1H); 3.95 (d, 1H).
Physicochemical data for the isomer (-) mass spectroscopy: MH + = 470.9 (FAB); [α] 25 D = -41.8 ° (c = 0.328 EtOH); partial 2 H NMR (CDCl 3, 400 MHz): 8.38 (s, 1 H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1H); 3.95 (d, 1H).
EXAMPLE OF PREPARATION 11 [racemic, as well as the R - (+) and S (-) isomers] Treat the ethyl ester of 4- (8-chloro-3-bromo, 5,6-dihydro-HH-benzo [5,6] cyclohepta) [1,2-b] pyridin-1-ylidene) -1-piperidine-1-carboxylic acid through practically the same procedure as described in preparation example 6, steps AL, for car as product of step C, racemic compound of the title, and as the products of step B the R - (+) isomer and the S - (-) isomer of the title compound. Physicochemical data for the R - (+) isomers: C NMR (CDCl 3), 155.8 (C) 146.4 (CH); 140.5 (CH); 140.2 (CH); 136.2 (CH); 135.3 (CH); 134.4 (C); 132.0 (CH); 129.9 (CH); 125.5 (CH); 119.2 (CH); 79.1 (CH); 52.3 (CH2); 52.3 (CH); 45.6 (CH2); 30.0 (CH2); 29.8 (CH2); [a] 25D = + 25.8 ° (8.90 mg / 2mL MeOH). Physicochemical data for the S - (-) isomer: 13C NMR (CDCl 3), 155.9 (C) 146.4 (CH); 140.5 (CH); 140.2 (CH); 136.2 (CH); 135.3 (CH); 133.3 (C); 132.0 (CH); 129.9 (CH); 125.5 (CH); 119.2 (CH); 79.1 (CH); 52.5 (CH2); 52.5 (CH); 47.5 (CH2); 30.0 (CH2); 29.8 (CH2); [a] 25D = -27.9 ° (8.90 mg / 2mL MeOH).
EXAMPLE OF PREPARATION 12 Dissolve 9.90 g (18.9 mmol) of the product of Preparation Example 7, Step B, in 150 mL of CH2C12 and 200 mL of CH3CN and heat to 60 ° C. Add 2.77 g (20.8 mmol) of N-chlorosuccinimide and heat at reflux for 3 h, monitor the reaction by TCL (30% EtOAc / H20). Add an additional 2.35 g (10.4 mmol) of N-chlorosuccinimide and heat 45 minutes more. Cool the reaction mixture to room temperature and extract with 1N NaOH and CH2C12. Dry the CH2C12 layer on MgSO4, filter and purify by flash chromatography (1200 ml in normal phase silica gel, eluting with 30% Et0Ac / II20) to obtain 6.24 g of the desired product, m.p. 193-195.4 ° C.
Step B: To 160 ml of concentrated HCl at -10 ° C add 2.07 g (30.1 mmol) of NaN02 and stir for 10 minutes. Add 5.18 g (10.1 mmol) of the product from step A and heat the reaction mixture from -10 ° C to 0 ° C for 2 hours. Cool the reaction to -10 ° C, add 100 ml of H3PO; and let it rest during the night. To extract the reaction mixture, pour over crushed ice and basify with 50% NaOH / CH2Cl2. Dry the organic phase over MgSO4, filter and concentrate to dryness. Purify by flash chromatography (600 ml normal phase silica gel, eluting with 20% EtOAc / hexane) to obtain 3.98 g of the product. Mass spectroscopy: MH + = 497.2.
Step C: Dissolve 3.9 g of the product from step B in 100 ml of concentrated HCl and reflux overnight. Cool the mixture, basify with 50% w / w NaOH and extract the resulting mixture with CH2C12. Dry the CH2C12 layer over MgSO4, evaporate the solvent and dry under vacuum to obtain 3.09 g of the desired product. Mass spectroscopy: MH + = 424.9.
Step D: Using a procedure similar to that described in Preparation Example 8, 1.73 g of the desired product is obtained, m.p. 169-6-170- .1 ° C; [a] 25D = + 48.2 ° (c = 1, MeOH).
Example 1 3 (R) - [2- (4- (3-bromo-8, 10-dichloro-6-l, dihydro-5-H-benzo [5,6] cyclohepta [1,2- b] pyridine- ll-il) -1-piperidinyl] -2-oxoethyl] -1- pyrrolidinecarboxamide Step 1: 1, 1-dimethylethyl-3 (R) - [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [ 1.2-b] pyridin-1-yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinecarboxylate.
Dissolve 1.0 g (2.34 mmol) of compound 5 (preparation example 12) in 20 ml of DMF, stir at room temperature and add 1.18 g (11.7 mmol) of 4-methylmorpholine, 0.7 g (3.65 mmol) of DEC, 0.494 g 3.65 mmol) of HOBT, and 0.8 g (3.51 mmol) of 3. Stir the mixture at room temperature for 2 days, then concentrate in vacuo to a residue. Perform the partition of the residue between CH2C12 and water, wash the organic phase successively with saturated NaHC03 (aqueous) and brine. Dry the organic phase over MgSO4 and concentrate in vacuo to a residue. Perform chromatography of the residue (silica gel, 2% CH30H / CH2C1 + NH3) to give 1.15 g of the title compound from step 1. mass spectroscopy: MH = 639; partial + H NMR) CDCl 3, 200 MHz): 8.42 (d, 1H); 7.45 (s, 1H); 7.28 (d, 1H); 7.08 (s, 1H); 4.88 (d, 1H); 4.45 (d, 1H); 1.45 (s, 9H).
Step 3 (R) - [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine-ll- il) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidine Combine 1.15 g of 6a and 50 ml of CH2C12 / cool to 0 ° C and add 50 ml of TFA. Stir the mixture for 4 h at 0 ° C, then concentrate in vacuo. Add water until a resulting residue is obtained and adjust to pH 9 with 1 N NaOH (aqueous). Extract with CH2Cl2, dry over MgSO4 and concentrate in vacuo to give 0.758 g of product 7a. Mass spectroscopy: MHP = 538 (Fab). Partial H NMR (CDC13, 200 MHz): 8.4 (d, 1H); 7.51 (s, 1H); 7.25 (d, 1H); 7.05 (s, 1H); 4.85 (d, 1H); 4.5 (d, 1H).
Step 3: Combine 0.319 g (0.51 mmol) of 7a and 20 ml of CH2C12, add 1.6 ml (11.8 mmol) of (CH3) 3SiNC0 and stir the mixture for 2 days at room temperature. Add 10 ml of NaHCO3 (aqueous), extract with CH2C12, wash with brine and dry over MgSO4, concentrate in vacuo to a residue and perform chromatography (silica gel, gradient 2.5%, 5.0%, then 7.5% CH30H / CH2C12 + 10% NH4OH) to obtain 0. 196 g of the title compound, m.p. 147-150 ° C; mass spectroscopy: MH + = 580.9 (Fab); partial 1 NMR (CDCl 3, 200 MHz): 8.45 (d, 1H); 7.52 (s, 1H); 7.3 (d, 1H); 7.1 (s, 1H); 4.85 (d, 1H); 4.52 (d, 1H); 4.35 (bs, 2H).
Example 2 (S) - [2- (4- (3-bromo-8,10-dichloro-6-l-dihydro-5-H-benzo [5,6] cyclohepta [1,2-b] pyridin-l-yl) ) -1-piperidinyl] -2-oxoethyl] -1- pyrrolidinecarboxamide Step 1: 1, 1-dimethylethyl-3 (S) - [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5-H-benzo [5, 6] -cyclohepta [ 1.2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinecarboxylate Use the procedure of example 1, step 1, except that (S) - (+) - 1-N-t-butoxycarbonyl pyrrodinyl-3-acetic acid (4) is used to prepare compound 6B, Mass spectroscopy MH 6J9; partial H NMR CDC13, 200 MHz '8.4: [?, 1H; 7 .. (s, 1H); 7.30 (d, 1H); 7.1 (s, 1H); 4. 88 (d, 1H); 4.55 (d, 1H) 1.45 (s, 9H) Step 2: (S) - [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine -ll-il) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidine React 1.0 [sic] of 6b with 50 ml of TFA using the same procedure as described in example 1, step 2, to give 0.66 g of compound 7b. Mass spectroscopy: M + = 538 (Fab) partial aH NMR (CDC13, 200 MHz): 8.41 (d, 1H); 7.52 (s, 1H); 7.25 (d, 1H); 7.1 (s, 1H); 4.85 (d, 1H); 4.52 (d, 1H).
Step 3 Combine 0.288 g (0.535 mmol) of 7b and 20 ml of CH2C12, add 1.44 ml (10.71 mmol) of (CH3) SiNCO and continue as described in example 1, step 3 to give 0.141 g of the title compound, m.p. = 145-150 ° C; mass spectroscopy: MH + = 580.9 (Fab) partial H NMR (CDC13, 200 MHz): 8.4 (d, 1H); 7.5 (s, 1H); 7.28 (d, 1H); 7.05 (s, 1H); 4.852 (d, 1H); 4.5 (d, 1H); 4.35 (bs, 2H): Example 3 3 (S) - [2- (4- (3, 10-bromo-8-dichloro-6-l, -dihiaro-5-H-benzo [5, 6] - cyclohepta [1,2-b] pyridine -ll- (R) -yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinecarboxamide [if c] Step 1: 1, 1-dimethylethyl-3 (S) - [2- (4- (3,10-dibrucho-8-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1 .2-b] pyridin-11 (R) -i 1) -1-piperidinyl] -2-oxoethyl] -l-pyrrolidinecarboxylate. React 1.31 g (2.7 mmol) of compound 8 with 0.76 g (3.3 mmol) of the compound 4 using practically the same procedure as described in example 1, step 1, to give 1.31 g of the product 9. Mass spectroscopy: M = 681 (Fab) Partial H NMR (CDC13, 200 MHz): 8.48 (d , 1H), 7.58 (s, 1H), 7.51 (d, 1H), 7.16 (d, 1H), 4.8 (d, 1H), 4.6 (d, 1H), 1.5 (s, 9H).
Step 2: 3 (S) - [2- (4- (3,10-dibromo-8-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine- 11 (R) -yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidine React 1.3 g of with 50 ml of TFA as described in example 1, step 2, to give 1.2 g of 10 p.f. = 160-162 ° C; mass spectroscopy: M + = 581.9 (Fab). 1 H NMR (CDCl 3 200 MHz): 8.42 (d, 1H); 7.55 (s, 1H); 7.5 (d, 1H); 7.12 (s, 1H); 4.88 (d, 1H); 4.52 (bd, 1H).
Combine 0.7 g (1.2 mmol) of 10 and 40 ml of CH2C12, then add 3.25 ml (24 mmol) of (CH3) SiNC0 and continue as described in example 1, step 3 to obtain 0.318 g of the title compound, m.p. = 148-150 ° C; mass spectroscopy: MH + = 625 (Fab).
Example 4 3 (S) - [2- (4- (3,10-dibromo-8-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine-11 (R) -yl) -1-piperidiniY 2-oxoethyl] -1-pyrrolidineacetamide NH2 Combine 0.1 g (0.172 mmol) of the product of Example 3, Step 2, 2 mL of DMF and 0.036 g (0.339 mmol) of Na 2 CO 3 at room temperature, then add 0.0249 g (0.18 mmol) of bromine acetamide and stir the Mix during the night. Add water and filter the solids. Wash the solids with water to give 0.075 g of the product. Mass spectroscopy: MH + = 639 (Fab); partial 1H NMR CDC13, 200 MHz): 8.44 (d, 1H); 7.55 (s, 1H); 7.5 (d, 1H); 7.15 (s, 1H); 5.5 (bs, 2H); 4.87 (d, 1H); 4.5 (d, 1H).
Example 5 3 (S) - [2- (4- (3,10-dibromo-8-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine-11 (R) -yl) -1-piperidinyl] 2-oxoethyl] -1-pyrrolidinmethylsulfonamide Combine 0.01 g (0.172 mmol) of the product of Example 3, step 2, 5 mL of CH2C12 and 0.034 g (0.048 mmol) of Et3N at room temperature, then add 0.021 g (0.189 mmol) of CH3SO2CI and stir the mixture overnight . Evaporate to dryness and purify the resulting residue by preparative chromatography, eluting with EtOAc to give 0.085 g of the product. Mass spectroscopy: M = 659.9 (Fab); partial? E NMR (CDC13, 200 MHz): 8.42 (d, 1H); 7.55 (s, 1H); 7.5 (d, 1H); 7.1 (s, 1H); 5.9 (d, 1H); 4.85 (d, 1H); 4.5 (d, 1H); 2.8 (s, 3H).
Example 6 2 (S) - [2- (4- (3-dibromo-8,10-dichloro-6-yl-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridin-ll -yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinecarboxamide Step 1: 1, 1-dimethylethyl-2 (S) - [2- (4- (3,10-dibromo-8-dichloro-6-dihydro-5-H-benzo [5,6] -cyclohepta [ 1.2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinecarboxylate: or Dissolve N-boc-homoprolin methyl ester (11) (0.56 g, 2.3 mmol) in EtOH (10 mL) and stir with IN LiOH (aqueous, 10 mL) at 50 ° C overnight. Adjust the pH with IN HCl to 4 and evaporate to dryness. Dissolve the residue in DMF (10 mL), and NMM (2 mL) and stir with DEC (0.66 g, 3.44 mmol), HOBT (0.47 g, 3.47 mmol), and compound 5 (1.47 g, 3.44 mmol). Evaporate to dryness. Extract with CH2C12 (100 mL) and wash with brine (2 x 100 ml). Dry over MgSO4 and evaporate to dryness to obtain an oily product. Flash chromatography on a column of silica gel, eluting with 50% hexane / EtOAc yields compound 12 (0.95 g) mass spectroscopy: MH + = 639; partial XH NMR (CDC13, 200 MHz): 8.42 (d, 1H); 7.54 (s, 1H); 7.31 (d, 1H); 7.09 (s, 1H); 4.85 (d, 1H); 4.53 (d, 1H); 1.45 (s, 9H).
Step 2: 2 (S) - [2- (4- (3-dibromo-8, 10-dichloro-6-li-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine- 11-yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidine 13 Combine 0.9 g of 12 and 10 ml of CH2C12, then cool to 0 ° C and add 10 ml of TFA. Stir the mixture for 3 h at 0 ° C, then concentrate in vacuo to a residue, add water and adjust the pH to 9 with INN NaOH (aqueous). Extract with CH2C12, dry over MgSO4 and concentrate in vacuo to obtain 0.538 g of 13. mass spectroscopy: M = 538 (FaB) partial XH NMR (CDC13, 200 MHz): 8.45 (d, 1H); 7.50 (s, 1H); 7.28 (d, 1H); 7.1 (s, 1H); 4.88 (d, 1H); 4.52 (d, 1H).
Step 3; Combine 0.2 g (0.37 mmol) of 13 and 10 ml of CH2C12, add 1.5 ml (11.07 mmol) of (CH3> SiNC0 and stir the mixture overnight at room temperature) Add 10 ml of NaHCO3 (aqueous) then extract with CH2CI2, wash with brine and dry over MgSO4, concentrate in vacuo to a residue and chromatograph (silica gel, gradient 2.5%, 5.0%, then 7.5% CH3OH / CH2Cl2 + 10% NH4OH) to obtain 0.132 g of the compound of the title Mass spectroscopy: MH + = 580.9 (Fab); partial 1H NMR (CDC13, 200 MHz): 8.4 (d, 1H); 7.5 (s, 1H); 7.28 (d, 1H); .05 (s) , 1H), 4.852 (d, 1H), 4.5 (d, 1H), 4.35 (bs, 2H).
Example 7 Phenyl 3- [2- [4- (3-dibromo-8,10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) ) -1-piperidinyl] -2-oxoethyl] -N-cyano-1-pyrrolidinecarboximidate Dissolve compound 7 (one equivalent) and diphenylcyanate carbonimidate (1.2 equivalents) in 2-propanol and heat the solution at 80 ° C under reflux and ba or N 2 for 24 h. Evaporate the mixture to dryness and chromatograph the product on a silica gel column (x 2.5 cm) using pure EtOAc as the eluent to obtain the title compound.
Example 8 3- [2- [4- (3-bromo-8, 10-dichloro-6-l, dihydro-5-H-benzo [5, 6] -cyclohepta [1,2-b] pyridin-ll-yl) -1-piperidinyl] -2-oxoethyl] -N- cyano-1-pyrrolidinecarboximidamide Dissolve the product of Example 7 in 2-propanol and add concentrated NH 4 OH. Stir the mixture at 25 ° C for 24 h and then evaporate to dryness. Triturate the residue with Et20 (2 x 250 ml) and discard the ether. Perform chromatography of the resulting product on a column of silica gel using 4% (10% concentrated NH 4 OH in CH 3 OH) -CH 2 Cl 2 as the eluent to obtain the title compound.
Example 9 Phenyl 3- [2- [4- p3-bromo-8, 10-dichloro-6-l-d? Hydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine-ll- il) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinecarboximidate Dissolve compound 7 (1 equivalent) in anhydrous CH2C12, add phenylcyanate (2 equivalents) and diisopropylethylamine (100 drops) and stir the mixture at 25 ° C during 15 minutes. Directly introduce the reaction mixture on a column of silica gel and elute with 10% increasing to 20% (10% concentrated NH 4 OH in CH 3 OH) -CH 2 C 12 to obtain the title compound.
Example 10 1- (3-bromo-8, 10-dichloro-6-l, dihydro-5-H-benzo [5, 6] cyclohepta [1,2-b] pyridin-ll-yl) -4- [4- ( 1-cyano-3-pyrrolidinyl) -acetyl] piperidine Dissolve the product of Example 9 (1 equivalent) in anhydrous THF. Add a dispersion in 60% NaH oil (4 equivalents) and stir the mixture at 25 ° C for 2 hours. Dilute the mixture with CH 2 Cl 2 V wash with 1 L NaOH. Dry the CH 2 C 12 layer over MgSO 4, filter and evaporate to dryness. Perform chromatography of the product on a column of silica gel eluting with 1.5% (10% concentrated NH40H in CH3OH) -CH2C12 to obtain the title compound.
Example 11 Phenyl 3- [2- [4- (3-bromo-8, 10-dichloro-6-l, dihydro-5-H-benzo [5, [6] -cyclohepta [1,2-b] pyridine-11- il) -1-piperidinyl] -2-oxoethyl] -N-sulfamoyl-1-pyrrolidinecarboximidate Method 1: Dissolve compound 7 (1 equivalent) and diphenylsulfamoyl carbonimidate (1.2 equivalents) [prepared as described in: M. Haake and B. Schummelfeder Synthesis, 753-758 (1991)] in 2-propanol and heating the mixture as described above in Example 7 to give the title compound.
Method 2: Dissolve the product of Example 9 (1 equivalent) in an inert anhydrous solvent such as CH 3 CN, benzene or toluene and add Et 3 N (2 equivalents) Cool the solution to 0 ° C and add sulfamoyl chloride (1.2 equivalents) [ prepared as described in: R. Appel and G. Berger, Chem. Ber., 91 (1958), pp. 1339-1341.] Shake the mixture at 0 ° C-25 ° C for 3 hours. CH2C12 and extract with 1 N NaOH, dry the CH2Cl2 layer over MgSO4, filter and evaporate to dryness, chromatograph the product on a column of silica gel (15 x 1 cm), eluting with 2%, increasing to 4% ( 10% NH 4 OH concentrated in CH 3 OH) - CH 2 Cl 2 to give the title compound.
Example 12 3- [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine-11- il) -1-piperidinyl] -2-oxoethyl] -N-sulfamoi1-1-pyrrolidinecarboximidamide Method 1: Dissolve the product of Example 11 in 2-propanol and add concentrated NH40H. Stir the mixture at 25 ° C for 24 hours and then evaporate to dryness. Triturate the residue with ET2O (2 x 250 ml) and discard the ether. The resulting product is chromatographed on a column of silica gel to give the title compound. Otherwise, the anhydrous ammonia in a suitable inert solvent such as CH 3 OH or THF can be used in place of NH 4 OH in the above reaction.
Method 2: Merge the product of Example 9 (1 equivalent) with sulfamide (4 to 10 equivalents) at 150 ° C at 180 ° C for 24 h. Purify the product on a column of silica gel to obtain the title compound. Otherwise, the reaction can be carried out using a suitable inert solvent such as 2-propanol at reflux temperatures.
Method 3: Merge the product of Example 10 (1 equivalent) with sulfamide (4 to 10 equivalents) at 150 ° C-180 ° C for 24 h. The product is purified on a column of silica gel to obtain the title compound.
Otherwise, the reaction can be carried out using a suitable inert solvent such as 2-propanol at the reflux temperatures.
Example 13 Phenyl 3- [2- (4- (3-bromo-8,10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) ) -1-piperidinyl] -2-oxoethyl] -N- (N-methylsulfamoyl) -1-pyrrolidinecarboximidate Method 1: Dissolve the product of Example 9 (1 equivalent) in an inert anhydrous solvent such as CH3CN, benzene or toluene and add Et3N (2 equivalents), cool the solution to 0 ° C and add N-methylsulfamoyl chloride (1.2 equivalents) [prepared as described in: JA Kloek and KL Leshinsky, J. Org. Chem., 41 (25) (1976), p 4028-4029]. Stir the mixture at 0-25 ° C for 3 h, extract, filter and evaporate to obtain the title compound.
Method 2: Dissolve compound 7 (1 equivalent) and diphenylmethyl sulfamoylcarbonimidate (1.2 equivalent) [prepared by the same procedure, only using methyl sulphamoyl chloride, as described in: A. Buschauer, Arch. Pharm. 377-378 (1987)] in 2-propanol and heat the mixture as described in example 7 to obtain the title compound.
Example 14 3- [2- [4- (3-Bromo-8, 10-dichloro-6-l-dihydro-5 H -benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) -1 -piperidinyl] -2-oxoethyl] -N- (N-methylsulfamoyl) -1-pyrrolidinecarboximidamide Dissolve the product of Example 13 in 2-propanol and add concentrated NH 4 OH. Stir the mixture at 25 ° C for 24 h and then evaporate to dryness. Triturate the residue with Et2? (2 x 250 ml) and discard the ether. The resulting product is subjected to chromatography on a silica gel column to obtain the title compound. Otherwise, the anhydrous ammonia in a suitable inert solvent such as CH 3 OH or THF can be used in place of NH 4 OH in the above reaction.
Example 15 Phenyl-3- [2- [4- (3-bromo-8,10-dichloro-6-l-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) -1-piperidinyl] -2-oxoethyl] -N- (N, N-dimethylsulfamoyl) -1-pyrrolidinecarboximidate Method 1 Dissolve the product of Example 9 (1 equivalent) in an inert anhydrous solvent such as CH 3 CN, benzene or toluene and add Et 2 N (2 equivalents). Cool the solution to 0 ° C and add N, N-dimethylsulfamoyl chloride (1.2 equivalents). Stir the mixture at 0-25 ° C for 3 h, extract, filter and evaporate to obtain the title compound.
Method 2: Dissolve compound 7 (1 equivalent) and diphenyldimethyl-sulfamoyl-carbonimidate (1.2 equivalents) in 2-propanol and heat the mixture as described in example 7 to obtain the title compound.
Example 16 Benzo [5, 6] -cyclohepta [1,2-blpindin-II-yl) -1-piperidinyl] -2-oxoethyl] -N- (N, N-dimethylsulfamoyl) -1-pyrrolidinecarboximidamide 2 Dissolve the product 15 in 2-propanol and add concentrated NH 4 OH. Stir the mixture at 25 ° C for 24 h and then evaporate to dryness. Triturate the residue with ET 0 (2 x 250 ml) and discard the ether. The resulting product is subjected to chromatography on a column of silica gel to obtain the title compound. Otherwise, the anhydrous ammonia in a suitable inert solvent such as CH 3 OH or THF can be used in place of NH 4 OH in the above reaction.
Example 17 3- [2- (4- (3-Bromo-8,10-dichloro-6-l-dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) -1-piperidinyl] -2-oxoethyl] -N-hydroxy-1-pyrrolidinecarboximidamide Method 1: Dissolve the product of Example 9 (1 equivalent) in CH 3 OH to prepare an aqueous solution of hydroxylamine by dissolving hydroxylamine hydrochloride (1 equivalent in 50% NaOH). % (w / v) (1 equivalent) and add to the mixture, stir at 25 ° C for 18 h, evaporate the solution to dryness and triturate with water, filter the solid and purify on silica gel to obtain the title compound. .
Method 2: Otherwise, the product of example 10 can react as described in method 1 above to obtain the title compound.
EXAMPLE 18 3- [2- [4- (3-Bromo-8, 10-dichloro-6-l, dihydro-5H-benzo [5, 6] -cyclohepta [1,2-b] pyridin-ll-yl) -1 -piperidinyl] -2-oxoethyl] -N-methoxy-1-pyrrolidinecarboximidamide Method 1: Dissolve the product of Example 9 (1 equivalent) in CH 3 OH. Add an aqueous solution of methoxylamine [prepared by dissolving methoxylamine hydrochloride (1 equivalent) in 50% NaOH (w / v) (1 equivalent)] and stir the mixture at 25 ° C for 18 h. The solution is evaporated to dryness and triturated with water. The solid is filtered and purified on silica gel to obtain the title compound.
Method 2 The product of Example 9 (1 equivalent) and methoxylamine hydrochloride (1 equivalent) are dissolved in anhydrous pyridine and the mixture is stirred at 25 ° C for 2 hours. The mixture is evaporated to dryness and purified on silica gel to obtain the title compound.
Example 19 Fen? L-3- [2- (4- (3-bromo-? 10-dichloro-6-l-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridine- 11-yl) -1-piperidinyl] -2-oxoethyl] -N-carboxamido-1-pyrrolidinecarboximidate Compound 7 (1 equivalent) and diphenylcarboxa ido-carbonimidate (1.2 equivalents) [prepared, using urea in place of sulfonamide, as described in: M. Haake and B. Schummelfeder, Synthesis, 753-758 (1991)] are dissolved in 2-propanol and the solution is heated at 80 ° C under reflux and under nitrogen for 24 h. The mixture is evaporated to dryness and subjected to chromatography on a column of silica gel to obtain the title compound.
Example 20 3- [2- [4- (3-Bromo-8, 10-dichloro-6-l, -dihydro-5 H -benzo [5, 6] -cyclohepta [1,2-b] p? Ridin-11-yl) -1-piperidinyl] -2-oxoethyl] -N-carboxamido-1-pyrrolidinecarboximidamide The product of Example 19 is dissolved in 2-propanol and concentrated NH 4 OH is added. The mixture is stirred at 25 ° C for 24 h and then evaporated to dryness. The residue is triturated with Et 0 (2 x 250 ml) and the ether is discarded. The resulting product is subjected to chromatography on a column of silica gel to obtain the title compound. Otherwise, anhydrous ammonia in a suitable inert solvent, such as CH30H or THF, may be used in place of NH4OH in the above reaction.
Example 21 Phenyl-3- [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5H-benzo [5,6] -cidiohepta [1,2-b] pyridin-ll-yl) -1-piperidinyl] -2-oxoethyl] -N- (N ~ - ethylcarboxamido) -1-pyrrolidinecarboximidate The product of Example 9 (1 equivalent) is dissolved in anhydrous CH 2 Cl 2. Methyl isocyanate (2 equivalents) is added and the mixture is stirred at 25 ° C for 48 h. The mixture is worked up as in example 19, method 2 to obtain the title compound after chromatography on silica gel.
Example: 2 3- [2- [4- (3-bromo-8, 10-dichloro-6-l-dihydro-5H-benzo [5,6] -cyclohepta i 1.2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] -N- (N '-methylcarboxamido) -1-pyrrolidinecarboximidamide The product of Example 21 is dissolved in 2-propanol and concentrated NH 4 OH is added. The mixture is stirred at 25 ° C for 24 h and then evaporated to dryness. The residue is triturated with Et2? (2 x 250 ml) and the ether is discarded. The remaining product is subjected to chromatography on a column of silica gel to obtain the title compound. Otherwise, the anhydrous ammonia in a suitable inert solvent, such as CH 3 OH or THF, may be used in place of NH 4 OH in the above reaction.
Example 23 5- [3- [2- [4- (3-bromo-8, 10-dicyoro-6-li-dihydro-5H-benzo [5, 61-cyclohepta [1,2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] -1- pyrrodinyl] -3-amino-1,2,4-triazole The product of Example 7 (1 equivalent) is dissolved in CH 3 OH. Hydrazine hydrate (1 equivalent) is added and the mixture is stirred at 25 ° C for 1 hour. The mixture is evaporated to dryness and subjected to chromatography on silica gel to obtain the title compound.
Example 24 3- [3- [2- [4- (3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) ) -1-piperidinyl] -2-oxoethyl] -1- pyrrolidinyl] -5-amino-1,2,4-oxadiazole and 5- [3- [2- [4- (3-bromo-8,10-dichloro -6,11-dihydro-5H-benzo [5, 6] -cyclohepta [1,2-b] pyridin-1-yl) -1-piperiinyl] -2-oxoethyl] -1- pyrroiidinyl] -5-amino-1 2, 4-oxadiazole The product of Example 10 (1 equivalent) is dissolved in CH30H. Hydroxylamine (1 equivalent) is added and the mixture is stirred at 25 ° C for 1 h. The mixture is evaporated to dryness and chromatographed on silica gel to obtain the title compounds.
Example 25 n- [3- [2- [4- (3-bromo-8, 10-dichloro-6,1, -dihydro-5H-benzo [5, 6] -cyclohepta [1,2-b] pyridin -11-yl) -1-piperidinyl] -2-oxoethyl] -1- pyrrolidinyl] -N '-methyl-2-nitro-l-ethenamine Copper (I) chloride (1 equivalent) is dissolved in anhydrous CH3CN. To this solution, a solution of compound 7 (1 equivalent), 1-methylthio-1-methylamino-2-nitroethene (1 equivalent) and Et 3 N in anhydrous CH 3 CN is added dropwise over 10 minutes with stirring. The solid is filtered. The volume is reduced and CH2C12 is added. The mixture is washed with aqueous NaHC03 and the CH2C1 layer is dried over MgSO4, filtered and evaporated to dryness. The residue is purified on silica gel to obtain the title compound.
Example 26 Phenyl-3- [2- (4- (3-bromo-8,1n-dicyoro-6,1-l-dihydro-5 H -benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) ) -1-piperidinyl] -2-oxoethyl J-N- (methylsulfonyl) -1-pyrrolidinecarboximidate Compound 7 (1 equivalent) and diphenylmethylsulfonyl-carbonimidate (1.12 equivalent) [prepared as described in. A. Buschauer, Arch. Pharm., 377-378 (1987)] is dissolved in 2-propanol and the mixture is heated as described in example 7 to obtain the title compound.
Example 27 3- [2- [4- (3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) -1-piperidinyl] -2-oxoethyl] -N- (ethylsulfonyl) -1-pyrrolidinecarboximidamide The product of Example 26 is dissolved in 2-propanol and concentrated NH 40 H is added. The mixture is stirred at 25 ° C for 24 h and then evaporated to dryness. The residue is triturated with Et20 (2 x 250 ml) and the ether is discarded. The resulting product is subjected to chromatography on a column of silica gel to obtain the title compound. Otherwise, the anhydrous ammonia in a suitable inert solvent such as CH 3 OH or THF can be used in place of NH 4 OH in the above reaction.
Example 28 Phenyl-3- [2- [4- (3-bromo-8,10-dichloro-6,11-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridin-1-yl) -1-piperidinyl] -2-oxoethyl] -N- (benzoyl) -1-pyrrolidinecarboximidate Compound 7 (1 equivalent) and diphenylmethylbenzoyl carbonimidate (1.2 equivalent) [prepared as described in A: Buschauer, Arch. Pharm., 377-378 (1987)] are dissolved in 2-propane and the mixture is heated as described in Example 7 to obtain the title compound.
EXAMPLE 29 3- [2- [4- (3-Bromo-8, 10-dichloro-6,11-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridin-11-yl) -1 -piperidinyl] -2-oxoethyl] -N-benzoyl-1-pyrrolidinecarboximidamide The product of Example 28 is dissolved in 2-propanol and concentrated NH 4 OH is added. The mixture is stirred at 25 ° C for 24 h and then evaporated to dryness. The residue is triturated with Et20 (2 x 250 ml) and the ether is discarded. The resulting product is subjected to chromatography on a column of silica gel to obtain the title compound. Otherwise, anhydrous ammonia in a suitable inert solvent such as CH30H or THF can be used in place of NH4OH in the above reaction.
Example 30 (+) -4- i 3, 10 -dibromo-8-chloro-6,1-l-dihydro-5 H -benzo [5, 6] -cyclohepta [1,2-b] pyridine-11- (R) -il) -l - [[- l- (4-pyridinium; 3 (S) -pyridinyl] acetyl] piperidine Stir a mixture of compound 10 (1 equivalent), anhydrous DMF, 4-chloropyridine hydrochloride (2 equivalents) and anhydrous Na 2 CO 3 (2.2 equivalents) at 100 ° C for 5 days. Cool the mixture to room temperature, dilute with water, filter and wash the solids with water. Dilute the solids with CH2C12, wash with 1M HCl, then with INN NaOH and dry over anhydrous MgSO4. Filter and concentrate vacuum. Purify by preparative plate chromatography (silica gel) eluting with 5% CH3OH-CH2Cl2 and concentrated NH4OH.
Example 31 t +) -4- i 3, lO-dibromo-B-chloro-e, ll-dihydro-5H-benzo [5, 6] -cyclohepta [1,2-b] pyridin-11-yl) -i- [ [1- (dimethylphosphinyl) -3 (S) pyrrolidinyl] acetyl] piperidine Dissolve compound 10 (1 equivalent) and Et3N (5 equivalents) in anhydrous CH2C12 and add dimethylphosphinyl chloride (4 equivalents). After stirring at room temperature for 48 hours, dilute the solution with CH2C12, wash with 1M HCl, then wash with IN aqueous NaOH and dry over anhydrous MgSO4. Filter, concentrate in vacuo and purify the resulting residue by preparative plate chromatography (silica gel) eluting with 2% CH30H-CH2C12 and concentrated NH4OH to provide the title compound.
Example 32 (+) -4- (3, 10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] -cyclohepta [1,2-b] pyridinyl-1-yl) - 1- [[1- [2, 3, 4, 6-tetra-o-acetyl-1-beta-D-glucopyranosyl] -3 (S) -pyrrolidinyl] acetyl] piperidine Dissolve compound 10 (1 equivalent) in 1,4-dioxane and add anhydrous Na 2 CO 3 (2 equivalents) and tetraacetoxy bromo-α-D-glucose (0.15 g, 1.1 equivalents). After stirring at reflux overnight, concentrate the mixture in vacuo, dilute with CH 2 Cl 2, wash with 1M HCl, then wash with IN NaOH and dry over anhydrous MgSO 4. Filter, concentrate in vacuo and purify the resulting residue by preparative plate chromatography (silica gel) eluting with 2% CH3OH-CH2Cl2 and concentrated NH4OH to provide the title compound.
Example 33 3 (S) - [2- (4- (3, 10-bromo-8, 10-dichloro-6-l, dihydro-5-H-benzo [5,6] -cyclohepta [1,2-b] pyridine -ll-il) -1-piperidinyl] -oxoethyl] -1-acetylpyrrolidine Dissolve compound 7b (1 equivalent) in CH30H and stir with Et3N (2 equivalents) and acetic anhydride (2 equivalents) at room temperature overnight. Evaporate to dryness and chromatograph the residue on a column of silica gel eluting with 2% CH3OH-CH2Cl2 and concentrated NH4OH to provide the title compound.
Example 34 (+) -! - [[! - (aminoacetyl) -3 (S) pyrrolididinyl] acetyl] -4- (3, 10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5, 6] -cyclohepta [1,2-b] pyridin-ll-yl) -piperidine [sic] Step +) - I, 1-dimethylethyl-2- [3 (S) - [2- [4 - (3,10-dibromo-8-c Loro-6,11-dihydro-5H-benzo [5,6] ] -cyclohepta [1,2-b] pyridin-ll-yl) -1-piperidinyl] -2-oxoethyl] -1-pyrrolidinyl] -2-oxoethyl carbamate Compound 10 (1 equivalent) is combined with HOBT (1.5 equivalents), DEC (1.5 equivalents), N-BOC-glycine (1.5 equivalents), and anhydrous DMF, and the resulting mixture is stirred at room temperature under nitrogen for the night. The mixture is concentrated in vacuo and the resulting residue is diluted with CH2Cl2, washed with 1M HCl and 1M aqueous NaOH, then dried over anhydrous MgSO4. Filtration and concentration in the vacuum produces compound 14. Step 2: Compound 14 (1 equivalent) dissolved in anhydrous CH 2 C 12 is added with TFA and the resulting solution is stirred at room temperature for 1 hour. Aqueous 50% NaOH is added slowly followed by CH2C12 and brine. The mixture is stirred well, the organic phase is separated and dried over anhydrous MgSO 4. Filtration and concentration in vacuo yields the title compound.
Example 35 (S) - [2- (4- (3-bromo-8, 10-dichloro-6-l-dihydro-5-K-benzo [5,6] -cyclohepta [1,2-b] pyridine -ll-il) -1-piperidinyl] -2-oxoethyl] -1- ethylpyrrolidine Dissolve compound 7b (1 equivalent) in DMF and stir with Et3N (2 equivalents) and CH3Br (2 equivalents) at room temperature, overnight. Evaporate to dryness and chromatograph the residue on a column of silica gel eluting with 2% CH30H-CH2C12 and concentrated NH4OH to provide the title compound.
ESSAYS The PFT IC50 assays (protein farnesyl transferase inhibition, in vitro enzyme assay) and COS Cell IC50 (cell-based assay) were determined following the assay procedures described in WO 95/10516, published on April 20. 1995. GGPT IC50 (inhibition of geranylgeranyl transferase protein, in vitro enzyme assay), the Cell Mat assay, and anti-tumor activity (anti-tumor studies in vivo) can be determined by the assay procedures described in WO 95/10516. The description of WO 95/10516 is incorporated herein by reference thereto. The results are given in Table 1. In Table 1"Ex. No. means" example No "and" nM "means" nanomolar ".
To prepare the pharmaceutical compositions from the compounds described in this invention, the inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, granules, dispersants, capsules, pills and suppositories. The powders and tablets can be compressed from about 5 to about 70% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a wax of melting point or such as may be a mixture of fatty acid glycerides or cocoa butter first melt, and the active ingredient is dispersed homogeneously therein by means of agitation. The molten homogeneous mixture is then emptied into molds of suitable size, allowed to cool and thereby solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection can be mentioned. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas. Also included are solid form preparations which are proposed to be converted, shortly before use, into liquid form preparations for oral or parenteral administration. These liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administered transdermally. The transdermal compositions can take the forms of creams, aerosol lotions and / or emulsions and can be included in transdermal patches of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In this form, the preparation is subdivided into a unit dose containing suitable quantities of the active component, for example, an effective amount to achieve the desired purpose. The amount of the active compound in a unit dose of the preparation can be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg, according to the specific application. The actual dosage used may vary depending on the patient's requirements and the severity of the condition being treated. The determination of the appropriate dosage for a specific situation is within the skills of the technique. In general, treatment starts with smaller doses that are less than the optimal dose of the compound. After this, the dose is increased in small increments until the optimum effect is obtained under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired. The amount and frequency of the administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the physician considering factors such as the age, condition and size of the patient, as well as the severity of the symptoms that are treated. A common recommended dosage regimen is oral administration of 10 mg to 2000 mg / day, preferably 10 mg to 1 C00 mg / day, in 2 to 4 divided doses to block tumor growth. The compounds are non-toxic when administered within these dosage ranges. The following are examples of pharmaceutical dosage forms containing a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not limited to the examples provided.
EXAMPLE A Tablets Manufacturing method Mix ingredients No. 1 and 2 in a suitable mixer for 11-15 minutes. Granulate the mixture with ingredient No. 3. Crush the wet granules through a coarse mesh (eg, 1/4 inch, 0.63 cm) if necessary. Dry the wet granules. Sift dry granules if necessary and mix with ingredient No. 4 and mix for 10-15 minutes. Add ingredient number 5 and mix for 1-3 minutes. Compress the mixture to the appropriate size and weight in a suitable tabletting machine.
EXAMPLE B Capsules Method of manufacture Mix the ingredients numbers 1, 2 and 3 in a suitable mixer for 10-15 minutes. Add the ingredient number 4 and mix for 1-3 minutes. Fill the mixture into 2-piece hard gelatin capsules, suitable in a suitable encapsulating machine. Although the present invention has been described in conjunction with the specific embodiments set forth in the foregoing, multiple alternatives, modifications and variations thereof will be apparent to those skilled in the art. All these alternatives, modifications and variations are proposed to be within the spirit and scope of the present invention.

Claims (18)

14 CLAIMS A compound represented by the formula; or a pharmaceutically acceptable salt or solvate thereof, wherein: a, b, c or d represents N or NR 9 wherein R9 is O ', CH3 or - (CH2) nC? 2H where n is 1 to 3, and remaining groups a, b, c and d represent CR 1 or CR 2; or a, b, c, and d are independently selected from CR1 or CR2; R and R 'is independently selected from H, halo, -CF3, -OR10, -COR10, -SR10, -S (0) tR wherein t is 0, 1 or 2, -SCN, -N (R10) 2, -NR10R, -N02, -OC (0) R10, -C02R10, -OC02RU, -NC, -NHC (C) R10, -NHS02R10, -CONHR10, -CONHCH2CH2OH, -NR ^ COOR11, 1 -S? UC (O) OR11, -SRiXN (R75) 2 where each R5 is independently selected from H and -C (0) CR ",? Enzotriazol-1-yloxy, tetrazol-5-ylthio, tetrazol-5-ylthio substituted, alkynyl, alkenyl and alkyl, the alkyl or alkenyl group being substituted with halo, -OR or -C02R, R 3 and R 4 are independently selected from the group consisting of H, R 1 and R 2, or R 3 and R 4 together represent a C5-C7 fused or unsaturated ring fused to the benzene ring: R, R, R and R are independently selected from the group consisting of H, CF3, -COR, alkyl and aryl, with alkyl or aryl being optionally substituted with -OR1 , SR10, -S (0) tRU -NR10COORU, -N (R10) 2, -N02, -COR10, -OCOR10, -0C02R1: L, -C02R10, or OP03R10, or R5 is combined with R6 which represents = 0 or = S, or R 7 is combined with R8 to represent = 0 or = S; or R 5 is combined with R6 which represents = 0 or = S, or R7 is combined with R to represent = 0 or = S [sic]; R represents H, alkyl, aryl, or aralkyl; R represents alkyl or aryl; X represents N, CH or C, where C can contain an optional double bond (represented by the dotted line) to the carbon atom 11; the dotted line between the carbon atoms 5 and 6 represents an optional double bond, such that when the double bond occurs, A and B independently represent -PPJ, halo, -PPPX -3C02R and -0C (0) R, and when there is no double Ygadura between the carbon atoms 5 and b, A and B each independently represent (H, H), (-0R11, -OR11;, (H, halo), (halo, halo), (alkyl, H), (alkyl, alkyl), (H, -OC (0) R10), (H, -OR10), = 0, (aryl, H) and = NOR10, or A and B together are -0- (CH2 ) p-0- where p is 2, 3, or 4, and R represents: (1) -C (0) N (RÍOY; (2) -CH2C (O) N (R10) 2; (3) -S02 -alkyl, -S02-aryl, -S02-aralkyl, -S02-heteroaryl or -S02-neterocycloalkyl; (4) cyano; (5) an imidate represented by the formula: NR13 II C / OR12 wherein R 13 is selected from group consisting of H, CN, -S02-alkylo, -C (O -aryl, -SO2NR10R14, -C (O) NR10R14 and -OR10; R12 14 is aryl and R is independently selected from the group consisting of H, alkyl, aryl, and aralqu ilo; (6) an imidamido group of the formula: NR13 II C / NR10R15 wherein R and R are as defined above; R15 is alkyl, aryl, aralkyl, cycloalkyl, heteroaplc, heteroaralkyl, or heterocycloalkyl; (7) an l-amino-2-n-troethylene derivative of the formula: C IIHN02 / NHR10; (8) -C (0) R 1, wherein R is alkyl, aralkyl or heteroaryl; (9) -C (0) -0-Rl0; 10 ' .17 wherein R is selected from the group consisting of H, alkyl, aralkyl, and heteroaralkyl; R and R each are selected independently from the group consisting of: H; -C (0) 0R, wherein R represents alkyl, aralkyl, and heteroaralkyl; -S02R wherein R is selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; -C (0) R; C 1-6 alkyl, alkaryl; and C_6 cycloalkyl; and R is 0, 1 or 2; (11) alkyl, aryl, aralkyl, cycloalkyl; heterocycloalkyl or heteroaryl; (12) -SO2NR10R14; (13) -P (O) (R10) 2; 141 jn sugar group of the formula # 7 ^ 6 wherein R "and R" are independently selected from the group consisting of H, alkyl (Ci-C?), Aryl and aryl 3 24? 5 '7 alkyl (Ci-Ce); and R ", R, R ~ and R are independently selected from the group consisting of H, (Ci-C6) alkyl, arylalkyl (C? -C6), -C (O) alkyl (C? -C6) and -C (O) aryl; (1.5) -CH2C (0) 0R, wherein R is selected from the group consisting of H, alkyl, aryl and heteroaryl; 2. The compound of claim 1, wherein R2 is H; R1 is Br or Cl; R3 is Cl or Br; R4 is H, Br or Cl; Rp R6, R7 and R8 are H, A and B are each H2; and the optional double bond between C5 and C6 is absent. 3. The compound of any of claims 1 or 2, wherein R is -C (0) N (R10) z, -CH2C (0) N (R10) 2 or -S02-alkyl, wherein F, '° is H and alkyl is methyl. 4. The compound of any of claims 1, 2 or 3, wherein X is CH. 5. The compound of claim 1 represented by the formula: wherein R ", R 'and R are independently selected from halo, and A, B, X and R are as defined in claim 1. 6. The compound of claim 5, wherein R1 is Br or Cl; "and R4 are independently selected from the group consisting of Br and Cl; A and B each are H2; and the optional link between C5 and C6 is absent. 7. The compound of claim 6 wherein R1 is Br; R3 is Cl; and R4 is Br or Cl. The compound of claim 7, wherein R is -C (O) N (R10) 2, -CH2C (0) N (R1p2 or -S02-alkyl, wherein R10 is H and alkyl is methyl 9. The compound of claim 1 is selected from the group consisting of a pharmaceutically acceptable salt or solvate thereof 10. A pharmaceutical composition for inhibiting abnormal cell growth containing an effective amount of the compound of any of the claims 1 to 9 in combination with a pharmaceutically acceptable carrier. 11. The use of a compound of any of claims 1 to 9 for the preparation of a medicament for the treatment of tumor cells expressing an activated ras oncogen. The use of claim 11, wherein the treated cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, tumor cells of the epidermal carcinoma, tumor cells of bladder carcinoma or colon tumor cells. 13. The use of a compound of any of claims 1 to 9 for the preparation of a medicament for the treatment of tumor cells, wherein the Ras protein is active as a result of the oncogenic mutation in genes other than the Ras gene. 14. The use of a compound of any of claims 1 to 9 for the preparation of a medicament for inhibiting farnesyl protein transferase. 15. A method of treating tumor cells expressing an activated Ras oncogene consisting of administering an effective amount of a compound of any of claims 1 to 9. 16. The method of claim 15, wherein the treated cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, follicular thyroid tumor cells, myelodyspiatic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells or tumor cells colon. 17. Ur tumor cell treatment method wherein the Ras proton is activated as a result of the oncogenic mutation in genes other than the Ras gene, which consists in the administration of an effective amount of a compound of any one of claims 1 to 9. 18. A method for inhibiting farnesyl protein transferase, which comprises administering an effective amount of a compound of any of claims 1 to 9.
MXPA/A/1999/002357A 1996-09-13 1999-03-11 Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases MXPA99002357A (en)

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