CA2143588A1 - Inhibitors of farnesyl protein transferase - Google Patents
Inhibitors of farnesyl protein transferaseInfo
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- CA2143588A1 CA2143588A1 CA002143588A CA2143588A CA2143588A1 CA 2143588 A1 CA2143588 A1 CA 2143588A1 CA 002143588 A CA002143588 A CA 002143588A CA 2143588 A CA2143588 A CA 2143588A CA 2143588 A1 CA2143588 A1 CA 2143588A1
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Abstract
Inhibition of farnesyl transferase, which is an enzyme involved in ras oncogene expression, is effected by compounds of the formula their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs, and solvates, wherein:
A1 and A2 are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl Y and Z are each independently -CH2- or -C(O)-;
R1 and R2 are each independently H or alkyl;
R1 and A1 taken together may be -(CH2)m-R3 is H, alkyl or phenyl;
J, K and L are each independently, N, NR4, O, S or CR5 with the provisos that only one of the groups J, K and L can be O or S, one or two of the groups J, K and L may be N or NR4, and at least one of the groups J or L must be N, NR4, O or S to form a fused five-membered heteroring;
the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring;
x is O or NR6;
R4 is H, alkyl or phenylalkyl;
R5 is H or alkyl;
R6 is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or C(O)R7;
R7 is H, alkyl, phenyl or substituted phenyl;
m is 3 or 4;
p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.
A1 and A2 are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl Y and Z are each independently -CH2- or -C(O)-;
R1 and R2 are each independently H or alkyl;
R1 and A1 taken together may be -(CH2)m-R3 is H, alkyl or phenyl;
J, K and L are each independently, N, NR4, O, S or CR5 with the provisos that only one of the groups J, K and L can be O or S, one or two of the groups J, K and L may be N or NR4, and at least one of the groups J or L must be N, NR4, O or S to form a fused five-membered heteroring;
the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring;
x is O or NR6;
R4 is H, alkyl or phenylalkyl;
R5 is H or alkyl;
R6 is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or C(O)R7;
R7 is H, alkyl, phenyl or substituted phenyl;
m is 3 or 4;
p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.
Description
21435~8 I~IB~TO~S OF FA~æSY~ PROTEIN T~NSFER~SP!
This invention relates to compounds that inhibit farnesyl-protein transferase and Ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through Ras and those associated with CAAX-cont~i n i ng proteins other than Ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds lS may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
7o The mammalian ras gene family comprises three genes, H-ras, K-ras and N-ras. The Ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and 2~ differentiation. Overproduction of normal Ras proteins or mutations that inhibit their GTPase activity can lead to uncon~rolled cell di.vision.
-The transforming activity of ~as is dependenton localization of the protein to plasma membranes.
This mem~rane b;n~i n~ occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and m~ tory step in this sequence of events is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (~PP) serves as the farnesyl group donor in this reaction. The Ras C-terminus contains a sequence motif termed a UCys-Aaa1-Aaa2-Xaa~ box (CAAX box~, wherein Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (Cys-186), there~y attaching the prenyl group on the protein via a thio-ether linkage.
In accordance with the present invention, a compound of the formula I
J ~ L
H(X)q ~ ~ H
\~ Y~ ~ N--~ N~ CO2H
HS
its enantiomers and diastereomers, and pharmaceutically acceptable salts, prodrugs and so~vates thereof inhibit S-farnesyl protein transferase, which is an enzyme Lnvolved in Ras _ 21435~8 _ 3 _ LD69 oncogene function. In formula I and throughout this specification, unless otherwise specified, the above symbols are defined as follows:
Al and A2 are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl;
Y and Z are each independently -CH2- or --C (O) --;
Rl and R2 are each independently H or alkyl;
Rl and Al taken together may be ~(CH2)m-;
R3 is H, alkyl or phenyl;
J, K and L are each independently, N, NR4, O, S or CR5 with the provisos that only one of the groups J, K and L can be O or S, one or two o~ the groups J, K and L may be N or NR4, and at least one ~ the groups J or L must be N, NR4, 0 or S to form a used five-membered heteroring;
the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring;
X is O or NR6;
R4 is H, alkyl or phenylalkyl;
R5 is H or alkyl;
R6 is H, alkyl, phenyL, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or ~ -C~o)R7;
R7 is H, alkyl, phenyl or substituted phenyl;
m is 3 or 4;
p is 0, l or 2; and q is 0 or l, with the proviso that when p is 0 0, q is also 0.
-_ 4 _ LD69 Listed below are definitions of various termsused to descri~e this invention. These definitions apply to the terms as they are used throughout this speci~ication, unless otherwise limited in specific instances, either individually or as part of a larger group.
The terms ~alkyl~ and "alk-" refer to straight or branched chain unsubstituted hydrocarbon groups of 1 to 7 carbon atoms. The expression '~lower alkyl~ refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term "substituted alkyl~ refers to an alkyl group substituted by, for example, one to four substituents such as halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino. alkylamino, dialkyl~mino, alkanoyl~mino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sul~onamido, nitro, cyano, carboxy, carbamyl, N-hydroxycarbamyl.
alkoxycarbonyl, phenyl, substituted phe~yl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term ~halogenu or ~halo~ refers to fluorine, chlorine, bromine and iodine.
The term ~alkoxy~ refers to alkyl-O-.
The term ~alkanoyl" refers to alkyl-C(O)-.
The term ~alkanoyloxyu refers to alkyl-C(O)-O-.
The terms ~alkylamino~ and n dialkylamino~
refer to (alkyl)NH- and (alkvl)2N-, respectively.
The term ~alkanoylamino~ refers to alkyl-C(O)-NH-.
The term ~alkylthio~ refers to alkyl-S-.
The term ~'alkylthiono~ refers to alkyl-S(0)-.
The term ~alkylsulfonyl~ refers to alkyl-S(O)2--S The term ~carbamyl~ refers to -C(0)NH2.
The term "alkoxycarbonyl" refers t~
alkyl-O-C(O)-.
The term ~substituted phenylU refers to a phenyl group substituted by, for example, one to four substituents such as alkyl, halo, ~ydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkyl~mi no, dialkyl ~mi no, alkanoyl ~mi no, thiol, alkylthio, nitro, cyano, carboxy, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, sulfonamido and the like.
The compounds of formula I form salts which are also within the scope of this invention.
Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
The compounds of formula I may form salts with alkali metals such as sodium, potassium and Iithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
Such salts may be obtained by exchanging the car~oxylic acid protons in compound I with the desired ion in a medium in which the salt precipitates or in an a~ueous medium followed by e~aporation.
~ 2 ~ 8 8 When compound I comprises a basic moiety, such as amino or substituted amino, it may form salts with a variety of organic and inorganic acids.
Such salts include those ~ormed with hydrogen ch~oride, hydrogen bromide, meth~nesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, ~oluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting compound I in an equivalen~ amount of the acid in a medium in which the salt precipitates or in an a~ueous medium followed by evaporation.
In addition, zwitterions ("inner salts~) may be formed.
A compound of the formula I may also have prodrug forms. Any compound that will be converted Ln v vo to provide the bioactive agent (i.e., the compound of formula I) ls a prodrug within the scope and spirit of the invention. For exampie, compound I may be in the form o~ a prodrug having the formula \0/
H ( X ~ q Al ~--) H
\~ ~N Z~f N~CO~R9 / CH~)p 0 A2 wherein R8 is:
214~a~8 lower alkyl, such as methyl, ethyl and the like;
substituted lower alkyl, such as 2-(N-morpholine)ethyl and the like;
lower aralkyl, such as benzyl, biphenylmethyl and the like;
(acyloxy)alkyl, such as (pivalyloxy)methyl, 1-(propanoyloxy)-2-methyl-1-propyl and the like;
(aminoacyloxy)aroyloxyalkyl, such as ~la-glycyloxybenzoyloxymethyl and the like;
(aminoalkoxy)aroyloxyalkyl, such as ~aLa-2-[(N-morpholine)ethoxy]benzoyloxyme~hyl and the like;
substituted amides, such as N,N-di(2-hydroxyethyl)acetamido, 4-methylpiperazine-1-acetyl, 4-(2-hydroxyethyl)piperazine-1-acetyl and the like; or a dioxolanemethyl, such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl and the like;
and Rg is:
k~noyl, aroyl, acyloxyalkyl, acylaminoalkyl, alkylthio, phenylalkylthio, J O L
R8 ~
~(X~q A1 ~ ) H
Y~ ~N~ N~CO~R8 (CH2)p O A
~S
2143~88 H2N~J~
- OH
~CH2 and the like. ~Of course, one of R8 and R9 may be H while the other one of R8 and R9 is as described above.) Additionally, for a compound of formula I
where X is NR6, R6 and R9 may be ~oined to form a thiazolidine ring. (See, e.g., H. T . Nagasawa, et al., J. Me~. Chem., 27, 591 (1984)).
Further, for a compound of formula I where A2 is substituted alkyl of the formula -(C~2)WOH
(where w is 2 or 3), A2 may be joined with the car~oxyl group to form a lactone ring which can be opened L~ vivo to give a compound of formula I
where A2 is -(CH2)WOH (again where w is 2 or 3).
various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Decian of Pro~rllas, edited by H. Bundgaard, (Elsevier, lg85) and Metho~s in Fnzvmol oov, Vol .
~2, p. 309-396, edlted by K. Widder, et al.
(Academic Press, 19853;
b) A Texthook of ~7rua Desicrn an~ DeveloDment, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, ~Design and Application of Prodrugs,~l by ~. Bundgaard, p. 113-191 (1991~;
c) H. Bundgaard, A~v~nce~ Drua Del iverv Reviews, ~, 1-38 (1992);
d) H. Bundgaard, et al ., Jol~rn~l of Ph~r~ceutic~l Sciences, 77, 285 (1988); and g .
e) N. Kakeya, et al., Chem Ph~rm B~ , 692 (1984).
It should further be understood tha~ solvates (e.g., hydrates) of the compounds o~ formuia I are also within the scope of the present in~ention.
Methods of sol~ation are generally known in the art.
For compounds of the formula I, the following moieties are preferred:
A1 and A2 are each independently H or D-, L- or DL- -CH3, -cH(cH3)2~ -cH2cx(cH3)2~
-CH(CH3)CH2CH3, -C(CH3)3, -CH2OH, -CH2CH20H, -CH2~3 -CH2CH2CH2OH, -CH(OH)CH3, {:H2~ N~l ~H2 ~ OH ~ -C~2 CH2 C~2 CH2 MH2 ~2 CH2 CH2 NH~ NH2 N~
-CH2C(O)OH, -CH2CH2C(O)OH, -cH2c(o)NH2 -CH2CH3, -CH2CH2C(O)NR1OR11 where R10 and Rll are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6, -CH2CH2OCH3, -CH2CH2C(O)NHOH, -CH2SH, -cH2cH2sH~ -cH2cH2s(o)2NH2 or -CH2CH2SCH3.
The following moieties are particuiarly preferred:
~ 21~3S88 Al is L- -CH3, -cH(cH3)2~ -cH2cH(cH3)2/
-C(CH3)3, ~ , -CH(CH3 )CH2CH3, -CH2OH or -CH(OH)CH3;
A2 is L- -CH2CH2SCH3, -CH2CH20H, -CH2CH2CH20H, S -CH2CH2C(O)NRlO~ll where R10 and Rll are each, independently, H, alkyl, phenyl or phenylalkyl,-or RlO and Rll taken together are (-CH2)t- where t is an integer from 2 to 6, or -CH2CH20CH3;
the fused five-membered (substituted) heteroring is ~ , ~ , ~ , s~1 o,~ HN~1 N~ NH
, , or X is NR6;
Rl, R2, R3, R~, R6 and R7 are H; and p is 1.
The compounds of formula I are inhibitors of S-farnesyl protein transferase. ~hey are thus useful in the treatment of a variety of cancers, including (but not Limited to) the following:
- carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;
- hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma and Bur~etts lymphoma;
_ 2~3~88 - hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia;
- tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and - other tumors, including melanoma, sPminom~, tetratocarcinoma, neuroblastoma and glioma.
The compounds of formula I are especially useful in treatment of tumors having a high incidence of Ras involvement, such as colon, lung, and pancreatic tumors. By the a~mi n i ~tration of a composition having one (or a combination) of the compounds of this invention, development of tumors in a m~m~Alian host is reduced.
Compounds of formula I may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through Ras, e.g., neuro-fibromatosis.
Compounds of formula I may also be useful in the treatment of diseases associated with CAAX-cont~ining proteins other than Ras (e.g., nuclear lamins and transducin) that are also post-translationally modified by the enzyme farnesyl protein transferase.
Compounds of formula I may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase), and thus be effective in the treatment of diseases associated with other prenyl modifications (e.g., geranylgeranylation~ of proteins (e.g., the rap, rab, rac and rho gene products and the like). For example, they may find use as drugs against Hepacitis delta virus (HDV) infections, as suggested by the recent finding thac geranylgeranylation of the large isoform of the ~ 2143588 delta antigen of HDV is a requirement for productive viral infection [J. S. Glenn, et al., Science, 25~, 1331 (1992)].
The compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formula I may be used sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
The compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous or subcutaneous ;ni~tration. The pharmaceutical composition can be formulated in a classical m~nnPr using solid or liquid vehicles, diluents and additives appropriate to the desired mode of A~mi ni stration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the l_ke.
These compounds may be a~minictered in a dosage range of about 0.05 tO 50 mg/kg~day, preferably less than 50 mg/kg/day, in a single dose or in 2 to 4 divided doses.
A compound of formula III below, wl~erein prol is an amine protecting group (e.g., t-butyloxy-carbonyl (Boc), benzyloxycarbonyl (Cbz) and the like):
2143~88 III
J~j~jL
R3_~ >
Pro l~ N~ OH
can be coupled with a carboxylic acid protected derivative o~ an amino acid of formula rv:
IV
H~N~ H~CO,Pro~
to form a compound of formula V below, wAerein pro2 is a carboxylic acid protecting group (e.g., alkyl, benzyl, p-methoxybenzyl and ~he like):
V
~ N ~ N~_~CO,Pro~
Pro n T
O A-For additional examples of amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T.W.
Greene and P.G.M. wuts, ~Protective Groups in Organic Synthesis~, Second Edition, John Wiley &
Sons, New York, '99l.
A variety of coupling agents may be used for this coupling, including l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorlde (E~CI~ ~ith l--~14353~
hydroxybenzotria~oie ( HOBT ), dicyclohexyl-carbodiimide (DCC) with ~OBT, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate (BOP) with or without ~OBT, carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride), isopropylchloroformate (IPCF) and the like.
Compounds of the formula IV are known in the art. See, for example, R. M. Williams, I'Synthesis of Optically Active a a-Amino Acids," Pergamon Press, Oxford, 1989.
Compounds of formula II~ can be prepared by methods known in the art. For example, for compounds of formula III wherein 1) J is -CH-, K is -CH- and L is S, see J. P. Maffrand, U.S. Patent No.
This invention relates to compounds that inhibit farnesyl-protein transferase and Ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through Ras and those associated with CAAX-cont~i n i ng proteins other than Ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds lS may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
7o The mammalian ras gene family comprises three genes, H-ras, K-ras and N-ras. The Ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and 2~ differentiation. Overproduction of normal Ras proteins or mutations that inhibit their GTPase activity can lead to uncon~rolled cell di.vision.
-The transforming activity of ~as is dependenton localization of the protein to plasma membranes.
This mem~rane b;n~i n~ occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and m~ tory step in this sequence of events is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (~PP) serves as the farnesyl group donor in this reaction. The Ras C-terminus contains a sequence motif termed a UCys-Aaa1-Aaa2-Xaa~ box (CAAX box~, wherein Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (Cys-186), there~y attaching the prenyl group on the protein via a thio-ether linkage.
In accordance with the present invention, a compound of the formula I
J ~ L
H(X)q ~ ~ H
\~ Y~ ~ N--~ N~ CO2H
HS
its enantiomers and diastereomers, and pharmaceutically acceptable salts, prodrugs and so~vates thereof inhibit S-farnesyl protein transferase, which is an enzyme Lnvolved in Ras _ 21435~8 _ 3 _ LD69 oncogene function. In formula I and throughout this specification, unless otherwise specified, the above symbols are defined as follows:
Al and A2 are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl;
Y and Z are each independently -CH2- or --C (O) --;
Rl and R2 are each independently H or alkyl;
Rl and Al taken together may be ~(CH2)m-;
R3 is H, alkyl or phenyl;
J, K and L are each independently, N, NR4, O, S or CR5 with the provisos that only one of the groups J, K and L can be O or S, one or two o~ the groups J, K and L may be N or NR4, and at least one ~ the groups J or L must be N, NR4, 0 or S to form a used five-membered heteroring;
the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring;
X is O or NR6;
R4 is H, alkyl or phenylalkyl;
R5 is H or alkyl;
R6 is H, alkyl, phenyL, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or ~ -C~o)R7;
R7 is H, alkyl, phenyl or substituted phenyl;
m is 3 or 4;
p is 0, l or 2; and q is 0 or l, with the proviso that when p is 0 0, q is also 0.
-_ 4 _ LD69 Listed below are definitions of various termsused to descri~e this invention. These definitions apply to the terms as they are used throughout this speci~ication, unless otherwise limited in specific instances, either individually or as part of a larger group.
The terms ~alkyl~ and "alk-" refer to straight or branched chain unsubstituted hydrocarbon groups of 1 to 7 carbon atoms. The expression '~lower alkyl~ refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term "substituted alkyl~ refers to an alkyl group substituted by, for example, one to four substituents such as halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino. alkylamino, dialkyl~mino, alkanoyl~mino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sul~onamido, nitro, cyano, carboxy, carbamyl, N-hydroxycarbamyl.
alkoxycarbonyl, phenyl, substituted phe~yl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term ~halogenu or ~halo~ refers to fluorine, chlorine, bromine and iodine.
The term ~alkoxy~ refers to alkyl-O-.
The term ~alkanoyl" refers to alkyl-C(O)-.
The term ~alkanoyloxyu refers to alkyl-C(O)-O-.
The terms ~alkylamino~ and n dialkylamino~
refer to (alkyl)NH- and (alkvl)2N-, respectively.
The term ~alkanoylamino~ refers to alkyl-C(O)-NH-.
The term ~alkylthio~ refers to alkyl-S-.
The term ~'alkylthiono~ refers to alkyl-S(0)-.
The term ~alkylsulfonyl~ refers to alkyl-S(O)2--S The term ~carbamyl~ refers to -C(0)NH2.
The term "alkoxycarbonyl" refers t~
alkyl-O-C(O)-.
The term ~substituted phenylU refers to a phenyl group substituted by, for example, one to four substituents such as alkyl, halo, ~ydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkyl~mi no, dialkyl ~mi no, alkanoyl ~mi no, thiol, alkylthio, nitro, cyano, carboxy, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, sulfonamido and the like.
The compounds of formula I form salts which are also within the scope of this invention.
Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
The compounds of formula I may form salts with alkali metals such as sodium, potassium and Iithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
Such salts may be obtained by exchanging the car~oxylic acid protons in compound I with the desired ion in a medium in which the salt precipitates or in an a~ueous medium followed by e~aporation.
~ 2 ~ 8 8 When compound I comprises a basic moiety, such as amino or substituted amino, it may form salts with a variety of organic and inorganic acids.
Such salts include those ~ormed with hydrogen ch~oride, hydrogen bromide, meth~nesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, ~oluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting compound I in an equivalen~ amount of the acid in a medium in which the salt precipitates or in an a~ueous medium followed by evaporation.
In addition, zwitterions ("inner salts~) may be formed.
A compound of the formula I may also have prodrug forms. Any compound that will be converted Ln v vo to provide the bioactive agent (i.e., the compound of formula I) ls a prodrug within the scope and spirit of the invention. For exampie, compound I may be in the form o~ a prodrug having the formula \0/
H ( X ~ q Al ~--) H
\~ ~N Z~f N~CO~R9 / CH~)p 0 A2 wherein R8 is:
214~a~8 lower alkyl, such as methyl, ethyl and the like;
substituted lower alkyl, such as 2-(N-morpholine)ethyl and the like;
lower aralkyl, such as benzyl, biphenylmethyl and the like;
(acyloxy)alkyl, such as (pivalyloxy)methyl, 1-(propanoyloxy)-2-methyl-1-propyl and the like;
(aminoacyloxy)aroyloxyalkyl, such as ~la-glycyloxybenzoyloxymethyl and the like;
(aminoalkoxy)aroyloxyalkyl, such as ~aLa-2-[(N-morpholine)ethoxy]benzoyloxyme~hyl and the like;
substituted amides, such as N,N-di(2-hydroxyethyl)acetamido, 4-methylpiperazine-1-acetyl, 4-(2-hydroxyethyl)piperazine-1-acetyl and the like; or a dioxolanemethyl, such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl and the like;
and Rg is:
k~noyl, aroyl, acyloxyalkyl, acylaminoalkyl, alkylthio, phenylalkylthio, J O L
R8 ~
~(X~q A1 ~ ) H
Y~ ~N~ N~CO~R8 (CH2)p O A
~S
2143~88 H2N~J~
- OH
~CH2 and the like. ~Of course, one of R8 and R9 may be H while the other one of R8 and R9 is as described above.) Additionally, for a compound of formula I
where X is NR6, R6 and R9 may be ~oined to form a thiazolidine ring. (See, e.g., H. T . Nagasawa, et al., J. Me~. Chem., 27, 591 (1984)).
Further, for a compound of formula I where A2 is substituted alkyl of the formula -(C~2)WOH
(where w is 2 or 3), A2 may be joined with the car~oxyl group to form a lactone ring which can be opened L~ vivo to give a compound of formula I
where A2 is -(CH2)WOH (again where w is 2 or 3).
various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Decian of Pro~rllas, edited by H. Bundgaard, (Elsevier, lg85) and Metho~s in Fnzvmol oov, Vol .
~2, p. 309-396, edlted by K. Widder, et al.
(Academic Press, 19853;
b) A Texthook of ~7rua Desicrn an~ DeveloDment, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, ~Design and Application of Prodrugs,~l by ~. Bundgaard, p. 113-191 (1991~;
c) H. Bundgaard, A~v~nce~ Drua Del iverv Reviews, ~, 1-38 (1992);
d) H. Bundgaard, et al ., Jol~rn~l of Ph~r~ceutic~l Sciences, 77, 285 (1988); and g .
e) N. Kakeya, et al., Chem Ph~rm B~ , 692 (1984).
It should further be understood tha~ solvates (e.g., hydrates) of the compounds o~ formuia I are also within the scope of the present in~ention.
Methods of sol~ation are generally known in the art.
For compounds of the formula I, the following moieties are preferred:
A1 and A2 are each independently H or D-, L- or DL- -CH3, -cH(cH3)2~ -cH2cx(cH3)2~
-CH(CH3)CH2CH3, -C(CH3)3, -CH2OH, -CH2CH20H, -CH2~3 -CH2CH2CH2OH, -CH(OH)CH3, {:H2~ N~l ~H2 ~ OH ~ -C~2 CH2 C~2 CH2 MH2 ~2 CH2 CH2 NH~ NH2 N~
-CH2C(O)OH, -CH2CH2C(O)OH, -cH2c(o)NH2 -CH2CH3, -CH2CH2C(O)NR1OR11 where R10 and Rll are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6, -CH2CH2OCH3, -CH2CH2C(O)NHOH, -CH2SH, -cH2cH2sH~ -cH2cH2s(o)2NH2 or -CH2CH2SCH3.
The following moieties are particuiarly preferred:
~ 21~3S88 Al is L- -CH3, -cH(cH3)2~ -cH2cH(cH3)2/
-C(CH3)3, ~ , -CH(CH3 )CH2CH3, -CH2OH or -CH(OH)CH3;
A2 is L- -CH2CH2SCH3, -CH2CH20H, -CH2CH2CH20H, S -CH2CH2C(O)NRlO~ll where R10 and Rll are each, independently, H, alkyl, phenyl or phenylalkyl,-or RlO and Rll taken together are (-CH2)t- where t is an integer from 2 to 6, or -CH2CH20CH3;
the fused five-membered (substituted) heteroring is ~ , ~ , ~ , s~1 o,~ HN~1 N~ NH
, , or X is NR6;
Rl, R2, R3, R~, R6 and R7 are H; and p is 1.
The compounds of formula I are inhibitors of S-farnesyl protein transferase. ~hey are thus useful in the treatment of a variety of cancers, including (but not Limited to) the following:
- carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;
- hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma and Bur~etts lymphoma;
_ 2~3~88 - hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia;
- tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and - other tumors, including melanoma, sPminom~, tetratocarcinoma, neuroblastoma and glioma.
The compounds of formula I are especially useful in treatment of tumors having a high incidence of Ras involvement, such as colon, lung, and pancreatic tumors. By the a~mi n i ~tration of a composition having one (or a combination) of the compounds of this invention, development of tumors in a m~m~Alian host is reduced.
Compounds of formula I may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through Ras, e.g., neuro-fibromatosis.
Compounds of formula I may also be useful in the treatment of diseases associated with CAAX-cont~ining proteins other than Ras (e.g., nuclear lamins and transducin) that are also post-translationally modified by the enzyme farnesyl protein transferase.
Compounds of formula I may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase), and thus be effective in the treatment of diseases associated with other prenyl modifications (e.g., geranylgeranylation~ of proteins (e.g., the rap, rab, rac and rho gene products and the like). For example, they may find use as drugs against Hepacitis delta virus (HDV) infections, as suggested by the recent finding thac geranylgeranylation of the large isoform of the ~ 2143588 delta antigen of HDV is a requirement for productive viral infection [J. S. Glenn, et al., Science, 25~, 1331 (1992)].
The compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formula I may be used sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
The compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous or subcutaneous ;ni~tration. The pharmaceutical composition can be formulated in a classical m~nnPr using solid or liquid vehicles, diluents and additives appropriate to the desired mode of A~mi ni stration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the l_ke.
These compounds may be a~minictered in a dosage range of about 0.05 tO 50 mg/kg~day, preferably less than 50 mg/kg/day, in a single dose or in 2 to 4 divided doses.
A compound of formula III below, wl~erein prol is an amine protecting group (e.g., t-butyloxy-carbonyl (Boc), benzyloxycarbonyl (Cbz) and the like):
2143~88 III
J~j~jL
R3_~ >
Pro l~ N~ OH
can be coupled with a carboxylic acid protected derivative o~ an amino acid of formula rv:
IV
H~N~ H~CO,Pro~
to form a compound of formula V below, wAerein pro2 is a carboxylic acid protecting group (e.g., alkyl, benzyl, p-methoxybenzyl and ~he like):
V
~ N ~ N~_~CO,Pro~
Pro n T
O A-For additional examples of amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T.W.
Greene and P.G.M. wuts, ~Protective Groups in Organic Synthesis~, Second Edition, John Wiley &
Sons, New York, '99l.
A variety of coupling agents may be used for this coupling, including l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorlde (E~CI~ ~ith l--~14353~
hydroxybenzotria~oie ( HOBT ), dicyclohexyl-carbodiimide (DCC) with ~OBT, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate (BOP) with or without ~OBT, carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride), isopropylchloroformate (IPCF) and the like.
Compounds of the formula IV are known in the art. See, for example, R. M. Williams, I'Synthesis of Optically Active a a-Amino Acids," Pergamon Press, Oxford, 1989.
Compounds of formula II~ can be prepared by methods known in the art. For example, for compounds of formula III wherein 1) J is -CH-, K is -CH- and L is S, see J. P. Maffrand, U.S. Patent No.
4,147,787 issued April 3, 1979; 2) J is S, K is -CH-and L is -CH-, also see J. P. Maffrand, U.S. Patent No. 4,147,787 issued April 3, 1979; 3) J is S and the bond between K and L form one side of a fused phenyl ring, see, e.g., H. Xawakubo, et al., J. Me~.
Chem., ~, 3110 (1990); ~ J is NR4, and the bond between K and L form one side of a fused phenyl ring, see D. G. Harvev, ~t ai., J. Chem Soc., i53 (1941) and A. srossi, et al., ~. Med. Chem. 16, 418, (1973); 5) J and L are NR4, and K is CR5, see M.
Cain, et al . , Heterocv~les, 19, 1003 (1982); and 6) J is O, and the bond between K and L form one side of a fused phenyl ring, see S. ueki, e~ al ., U. S .
Patent ~Jo. 5,126,448 issued June 30, 1992.
A compound of formula v can be treated with a suitable N-deprotecting agent to proviàe the corresponding free amine of formula VI:
~ 2143588 VI
J ~ L
N~CO~Pro-O A
(The prol and pro2 protecting groups are chosen so that prol can be selectively remo~ed in the presence of Pro2).
An amine of formula VI can be coupled with a suitable amine-protected amino acid of formula VII
(wherein Pro3 is an amine protecting group~:
VII Al P ' OH
R ¦ ¦
R~ O
using an approprla~e coupling reagent (e.g., 30P-Cl) to form a compouna of formula VIII:
VIII
J ~ L
AL ~ > H
Pro ~ ~ N ~ N ~ C02Pro (Compounds of formula VII are known in ~he art.
See, for exampLe, R.M. '.~illiams, ~Synthesis of -21435~8 L~69 Optically Active a-Amino Acids,~ Pergamon Press, Oxford, 1989).
Compounds of formula VIII can also be prepared by coupling a C-terminal protected amino acid of the formula IX (wherein Pro4 is a carboxylic acid protecting group):
IX
\~ O~L
R~
N ~ OPro4 with an amine-protected amino acid of formula VII
above to provide a compound of formula X:
J O L
A~ ~
Pro ~ N ~ ~ ~ OPro4 IL R2 ll R o o The Pro~ protecting group o~ compound x can be selectively removed by me~hods known in the art to provide a compound o~ formula XI below:
~ 21~3~8 XI
Pro~ ~ OH
(The Pro3 and Pro4 protecting groups are chosen so that Pro4 can be selectively removed in the presence of Pro3).
Coupling of a compound of formula XI with an amino ester of formula IV would then pro~ide compound VIII.
A compound of formula VIII can be selectively N-deprotected by methods known in the art to pro~ide an amine of formula XII:
XII
2,.1R~
H~ ~ N ~ N ~ CO2Pro (The pro2 and Pro3 protecting groups are chosen so that Pro3 can be selectively removed in the presence of Pro2).
Coupling of an amine of formula XII with an acid of formula XIII (wherein X is optionally protected and Pro5 is a thiol protecting group such as trityl):
~ 2143588 XIII
H (X~ l~
`f OH
( CH2 ) p ProsS
with a suitable coupling agent provides a compound 5 of formula xrv XIV
H(X~
~cyl~ R o O
Pro5S
3eprotection o~ the pro2 and ProS groups of XIV, and removal of the optionai protecting group on X, then provides a compound of formula I where Y
and Z are -C(O)-. (See T.W. Greene and P.G.M.
wuts, ~Protective Groups in Organic Synthesis", John Wiley & Sons, New York, l99l, for exemplary protectins groups for X, their formation and removal).
Alternatively, removal of the nitrogen protecting group (Pro3) from a compound of formula X gives an amine of formula XV:
2~13S88 XV
R O O
which can then be coupled with an acid of formula XIII to pro~ide a compound of formula XVI wherein X
is optionally protected:
XVI
J O L
H(X~
~ I ~ ~
( CH2 ) p O
Pro S
Selective deprotection o~ the Pro~ protecting group of XVI provides an acid of formula XVII:
XVII
.~3 H(XJ~ >
(CH2)p R O O
Pro'S
which can be coupled with an amine of formula IV to pro~ide a compound of formula XIV. Deprotection of the pro2 protecting group of XIV, and removal of the optional protecting group on X, then also provides a compound of formula I where Y and Z are --C ~O) --.
Further, a compound of formula I where Y and Z are -C(O)- can be prepared by automated solid phase peptide synthesis using methods that are well known in the art. See, for example:
a) M. Bodansky and A. Bodansky, ~The Practice of Peptide Synthesis~, springer-Verlag, Berlin/Heidelberg/New York/Tokyo, 1984i and b) J. M. Stewart and J. D. Young, "Solid Phase Peptide Synthesis~, Pierce C~emical Co., Rockport, Illinois, 1984.
In another process, an amino acid of formula VII (wherein Pro3 is a suitable amino protecting group) can be con~erted to the N-methoxy-N-methylamide of formula XVIII by methods known inthe art:
XVIII
Al fH3 Pro ~ N~ ~ C~ ~
Rl o A compound of formula XVIII can be reduced tO
an aldehyde of formula XIX by methods known in the art. (See, e.g., Fehrentz, et al ., Svnthe~is, ~76 (1983)):
- - -21435~8 XIX
Al Pro3~ ~CI~ ~ H
R' O
Alternatively, a compound of formula XIX can be prepared by reduction of a compound of formula VII with a reducing agent such as borane, followed by oxidation of the resulting alcohol using, for examp7e, the Swern method of oxidation. (See, e.g., Luly, et al., J. Or~. Ch~m., 52, 1487 (1987);
or Stanfield, et al., J. Or~. Chem~ 4~, 4797 (1981)). In yet another alternati~e, a compound of formula XIX can be prepared by reduction of an ester of a compound of formula VII with a reducing agent such as diisobu~ylaluminum hydride. See, e.g., Rich, et al ., ~ . Ora . Chem., 43, 3624 ( 1978).
An N-protected aldehyde of formula XIX can be reductiveLy aminated with an amine of formula VI to form a compound of formula xX using methods ~nown in the art (e.g., sorch, et al., ~. ~. Ch~. coc , ~, 2897 (1971)):
XX' ALR~
L~H
~ 2~3588 LD~9 A compound of formula XX can be treated with a suitable N-deprotecting agent to provide the corresponding free amine of formula XXI:
XXI
",i ~
R H O
(The pro2 and Pro3 protecting groups are chosen so that Pro3 can be selectively removed in the presence of Pro2).
A compound of formula XXI can be coupled with an acid of formula XXII (wherein X is optionally protected) using an appropriate coupling reagent tO
form a compound of formula XXII:
XXII
~(L
Pross Deprotection of the pro2 group of the compound of formula XXII, and removal of the optional protecting group on X, provides a compound of formula I where Y is -CtO~-, Z is -CH2-.
21~3~8 An acid of formula XIII (wherein X is optionally protected) can also be converted to the N-methoxy-N-methylamide of formula XXIII by methods known in the art (e.g., Fehrentz, et al ., Svnth~sis, 676 (1983)):
XXIII
~C~
C N- O
/ \
(CH~)p Pro S
A compound of formula XXIII can be selectively reduced to an aldehyde of formula xxrv by methods known in the art (e.g., r ehrentz, et al ., Svnthesis, 676 (1983)):
XXIV
H(X)~
C~
I H
(C~,)p Pro~S
An aldehyàe of formula XXIV can be reductiveiy aminated with an amine of formula XII to form a compound of formula XXV using methods known in the art (e.g., ~orch, et al ., J . ~m . Chem. Soc., ~, 2897 (1971)):
~ 3 5 8 8 - 2~ -XXV
J ~ L
H(X) H H ~1 ~ ~ H
N ~ C02Pro2 / CH2)p O A~
Pro~S
Deprotection of the Pro2, and removal of the optional protecting group on X, provides a compound of formula I where Y is -CH2-, Z is -C(O)-.
Alternatively, reductive amination o~ a compound of formula XXVI where pro6 is a carboxyLic acid protecting group:
XXVI
.;~,1 H~ ~ oPro~
1~n R' O
with a compound o f f ormula XXIV provides a compound of formula XXVII:
XXVII
H(X)~ V
OPro~
I 1~ R
(CH2)p 0 /
Pro'S
Selective deprotection of the pro6 group provides a compound o f f ormula XXVIII:
~ 21~3588 XXVIII
H(X) ~.H
( CH2 ) p Pro5S
which, on coupling with a compound of formula VI
(using, for example, BOP-Cl) provides a compound of S formula XX~.
By combining the appropriate steps above, one skilled in the art can also prepare a compound of formula I where both Y and Z are -CH2--Side-chain protecting groups may be used in these processes with amino acids ha~ing reactive functionalities, such as hydroxyl, carboxyl, amino, mercapto, guanidino, ; mi ~olyl, indolyl and the like. The particular protecting groups used for any amino acid residues depend upon the sidechains to be protected and are generally known in the art.
Exemplary sidechain protecting groups incLude acetyl, benzoyi, benzyl, t-butyl and the ike for hydroxyl; cyclohexyl, benzyl, methyl, ethyl, t-butyl and the like for carboxyl; benzyl, 4-methylbenzyl, 4-methoxybenzyl, acetyl, acetamidomethyl, triphenylmethyl (trityl) and the like for mercapto; t-butoxycarbonyl (Boc), benzyloxylcarbonyl (Cbz), ~-~(9~-Fluoren-~-ylmethoxy)carbonyl] (Fmoc~, phthaloyl (Pht), p-toluenesul~onyl (Tos), trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl (Teoc) and the like for amino; 2,4-dinitrophenyl, benzyloxymethyl, Tos, Boc, trityl and the like for imidazolyl; formyl, Cbz, Teoc, 2,2,2-trichloroethyl carbamate (TROC) and the like for indolyl; and tosyl, nitro, bis(1-adamantyloxycarbonyl) and the like for guanidino.
Side-chain protecting groups may be removed, if desired, by, for example, treatment with one or more deprotecting agents in an inert solvent or solvent mixture. For examples of protec~ing groups and suitable deprotecting agents, see M. Bodansky and A. Bodansky, ~The Practice of Peptide SynthesisU, springer-Verlag~ Inc. ~1984); and T. W.
Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis~, Second Edition, John Wiley Sons, New York, 1991.
The invention will now be further described by the following working examples, which are preferred embodiments of the invention. All temperatures are in degrees Celsius (C) unless otherwise indicated.
Compounds exemplified herein, which comprise a basic moiety such as an amine or substituted amine, may exist as a salt of an organic or inorganic acid. This information is not necessarily explicitly described in all the examples, but would be understood by those skilled in the arc. These examples are illustrative rather than limiting.
~ ~143~88 ~mn le N-[[5-[N-[(R)-2-Amino-3-mercaptopropyl]-L-valyl]-4,S,6,7-tetrahydrothieno~3,2-cipyridin-6-yl]-c~rhonvll-r,-methionine, trifllloro~cetAte (1:1) sAlt A. N2-~(1,1-Dime~hylethoxy)car~onyl]-N-methoxy-N-methyl-S-(triphenylmethyl)-r.-cvStein~mi ~le N-Butyloxycarbonyl-S-trityl-L-Cysteine (20.0 g, 43.14 mmol), 1-ethyl-3-(3-dimethyl~mi~opropyL) car~odiimide-~Cl (8.3 g, ~3.1 mmol) and 1-hydroxybenzotriazole hydrate (5.8 g, 43.1 mmol) were dissolved in dimethyl~ormamide (100 mL). N,O-Dimethylhydroxylamine hydrochloride (4.91 g, 50.6 mmol) and N,N-diiso~oy~lethylamine (6.13 g, 8.3 mL, 47.5 mmol) were then added. The reaction mixture was stirred ~or 5 hours at room temperature, poured into water (50 mL) and 2~ extracted with e~hyl acetate (3 x 200 mL). The combined organic layers were washed with water (3 x 500 mL) and brine (200 mL), dried magnesium sulfate, concentrated and chromatographed (silica gel, eluting with 40% ethyl acetate, 60% hexane).
Fractions containing the proàuct were collected and concentrated to yield Compound A as a white solid (19.95 g, 92%) B. N-[(1,1-Dimethylethoxy)car~onyl]-S-(trinhenYImethvl)-r.-cysteinAl Lithium aluminum hydride in tetrahydro~uran (lM, 59.3 mL, 59.3 mmol) was added dropwise to a solution of Compound A (25 g, ~9.4 mmol) in diethyi ether (500 mL) at -lSC, while keeping the .
temperature below -14C. The reaction was stirred at -15C for 30 minutes, quenched slowly with potassium hydrogen sulfate (134.4 g, 99.8 mmol) in water (400 mL), warmed to room temperature, and stirred for 1 hour. The organic layer was separated and washed sequentially with 10%
potassium hydrogen sulfate (1 x 200 mL), lN
hydrochloric acid (1 x 200 mL) and 10% sodium bicarbonate (1 x 300 mL). The organic layer was dried (magnesium sulfate), filtered and concentrated under ~acuum to a~ford the aldehyde Compound B (20 g, 90%), which was used withou~
further purification.
mp: 48-54C
TLC: Rf : 0.80 (1/1 hexane/ethyl acetate, visualization by W) MS: (M-H)- 446 IR: (KBr), 1713 cm~1 [a]D = + 16.0, ( c = 1.19 methanol) C. (R)-N-[2-[(1,1-Dimethylethoxy)carbonyl]-3-[(triphenyimethyl)thio3propyl]-1-valine, meth~] ester Acetic acid (2.6 mL, 44.74 mmol) was added eo a solution of Compound B 120 g, 44.74 mmoL) and L-valine methyl ester HCl (9.0 g, 53.7 mmol) in methanoi (50 mL). The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (2.8 g, 44.74 mmol) in tetrahydrofuran (50 mL) was added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with sodium bicarbonate (3.75 g, 44.74 mmol) in water (20 mL) and concentrated ~ , _ , .
under vacuum. The residue was dissolved in 10%
sodium bicarbonate (10 m~) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 9:1 hexane/acetone) to afford Compound C (17.7 g, 70%).
D. (R)-N-[2-[(1,1-Dimethylethoxy)carbonyl~-3-o r (tri~hen~lmethvl)th;ol~ro~vll-1-v~line A solution of lithium hydroxide (lN, 7.2 mL, 7.2 mmoi) and Compound C (2.0 g, 3.6 mmol~ in 2/2/1 tetrahydrofuran/dioxane/methanol (10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, and diluted with water (50 mL) and lN hydrochloric acid (11.1 mL). The aqueous mixture was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried (magnesium sulfate), filtered, concentrated under vacuum, and used without further purification to afford Compound D (2.08 g, 100%) as a white soiid.
mp: 155-i66C
TLC: Rf = 0.45 (9/1/0.05 chloroform~methanol/acetic acid, visualization by W) MS: (M+H)+ 549 E. 5-[(1,1-Dimethylethoxy)carbonyl~-4,5,5,7-tetrahyarothieno[3,2-cipyridine-5-carboxylic ~ci~
To a suspension of 6-carboxy-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.9 g, 4.9 mmol;
for preparation, see J. P. Maffrand, U.S. Patent No. 4,147,,87 issued April 3, 179) in dioxane (7 .
~ 2~3S~8 mL) at 0C was added 1~ sodium hydroxide (5 mL, 10 mmol) and water (5 mL). To the resulting clear solution was aàded soc-anhydride (1.53 g, 7.0 mmol) and the cold bath was removed. ~fter 1 hour, the reaction mixture was concentrated to hal~ the ~olume, and ethyl acetate (15 mL) and lN
hydrochloric acid (8 mL) were added with vigorou;s stirring. The aqueous layer was separated and extracted with ethyl acetate (10 mL). The organic layers were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to afford Compound E (i.52 g, 110% of theoretical).
~S (FAB), (M+H)+ = 284' lS F. N-[tS-[(1,1-Dimethylethoxy)carbon~l]-4,5,6,~-tetrahydrothieno~3,2-c~pyridin-6-vllc~rhon~ll-r-methionine methvl ester To a solution of Compound E (1.52 g) in dichloromethane (lS mL) at O~C under argon was added sequentially benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophospnate (2.21 g, ~.0 mmol), N-methylmorpholine (2.1 mL, 1 mmol) and the hydrochloride salt of L-me~hionine methyl ester (1.O g, S mmol). The reaction was allowed to warm to room temperature. ~fter 16 hours, the reaction mixture was washed successively with lN hydrochloric acid, saturated sodium bicarbonate and brine (lS mL each). Each aqueous layer was extracted separately with chloroform (10 mL). The organic layers were com~ined, dried (magnesium sulfate), iltered and concentrated.
The residue was purified by flash silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford Compound F (1.15 g).
2143~88 MS (CI), (M+H)+ = 429+
TLC : Rf 0.46 (50%, ethyl acetate in hexanes, visualized by W and ceric ammon. moiybdate) HPLC: YMC, S3, C18 (6 x 150 mm) column, 220 nm, 1.5 S mL/min: 0-90% aqueous methanol with 0.2% phosphoric acid, gradient over 30 minutes : Retention time :
28.2 and 28.3 minutes (two diastereomers) G. N-[[5-[N-[(R)-2-[(1,1-Dimethylethoxy)-carbonyl]-3-[(triphenylmethyl)thio]propyl]-L-valyl]-4,5,6,7-tetrahydrothieno[3,2-c~pyridin-6-yl]carbonyl]-~-methionine, methvl ester Anhydrous hydrochloric acid (4M in dioxane, 1~ 3 mL, 12 mmol) and triethylsilane (0.4 mL, 2.5 mmol) were added to Compound F (1.1 g, 2 57 mmol) at room temperature under argon. After stirring 1.5 hours, the volatiles were removed in vacuo and the residue was triturated with ether and dried in vacuo (1.0 g).
To the resulting amine hydrochloride (0.8 g) in dichloromethane (8 ~L) at 0C under argon was added the acid Compound D (1.0 g, 1.82 m~ol) and dimethylformamide (1 mL) to obtain a homogeneous 2~ solution. soP-cl (0.48 g, 1.9 mmol) and N,N-diisopropylethylamine (0.73 mL, 4.1 mmol) were added and the reaction mixture was stirred overnight at 5C. The reaction mixture was diluted with ethyl acetate (15 mL~ and washed sequentially with lN hydrogen chloride, saturated sodium bicar~onate and brine (10 mL eacA). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo . The r~sidue was purified by flash silica gel column c~romatography eluting with , ~ 2143~8 step gradient of 30%. 40% and 50~ ethyl acetate in hexanes to afford Compound G (240 mg, 15~), as a white foam.
In a separate, small scale experiment, S dimethyiformamide was not used as co-solvent. In this case, the yield of Compound G was 40%.
MS: (FAB) ~M+H)+ = 859+
TLC : Rf 0.51 (1:1, ethyl acetate in hexanes, visualized by W and ceric ammon. molybdate, shows two diastereomers when spotted very dilute).
HPLC: YMC, S3, C18 (6 x lS0 mm) column, 220 nm, ~.5 mL/min: 0-90% aqueous methanoi with Q.2% phosphoric acid, gradient over 30 minutes : Retention time :
30.9 minu~es.
1~
H. N-[[5-[N-[tR)-2-Amino-3-mercaptopropyl]-~-~alyl]-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-6-yl]carbonyi]-L-methionine, triflllQro~cet~e (1:1) s~lt ~0 To a solution of compound 5 (0.22 g, 0.26 mmoi) in methanol (1 mL) and tetrahydrofuran (2 mL) at room tempera~ure was added a~ueous lN lithium hydroxide (0.3 mL, a . 3 mmol). ~ter 8 hours, 1~
hydrogen chloride (l mL~ was added and the mixture was ex~racted with ethyl acetate (5 mL). The organic layer was dried (magnesium sulfa~e), filtered and concentrated in ~acuo to afford a white soiid (240 mg; MS (M+H)+ = 845+).
To a solution of the above solid (230 mg) ~n dichloromethane (1.2 mL) at room tempera~ure under argon was added triethylsilane (0.08 mL, 0.48 mmol) and trifluoroacetic acid (1 mL). After 1.5 hours, the volatiles were removed in vacuo and the residue was dissolved in deoxygena~ed 40% aqueous methanol.
21~3588 The precipitate formed was filtered through nylon 0.45 ~ filter and the filtrate was purified by RPHPLC (YMC, S10, C18, 30 x 500 mm column) eluting with a linear gradient of ~2%-66% aqueous methanol cont~i~ing 0.1% trifluoroacetic acid over 1 hour.
Appropriate fractions were collected and concentrated in vacuo to remo~e methanol. The r~aining solution was lyophili~ed to obtain the title compound (150 mg, 80%), as a white lyophilate.
m.p. 64-66C
MS:(FAB); (M+H)' = 502' HPLC: YMC, S3, C18 (6 x 150 mm) column, 220 nm, 1.5 mL/min: 10-90% a~ueous methznol with 0.2%
phosphoric acid, gradient over 30 minutes :
Retention time : 16.0 minutes [a~D = -16.2 (c= 0.6, methanol) Elemental analysis for C21H34N4O452. 1.2 ~2 2.05 trifluoroacetic acid ~ E
Calculated: 39.77 5.11 7.39 12.69 ~ound: 39.72 5.15 7.47 15.46 21~35~8 ~x;lmn le 2 (S~,R*)-N-[[2-[N-(2-Amino-3-merCaptOy ~yl)-L-valyl]-2,3,4,9-tetrahydro-lH-pyrido~3,4-b]indol-3-vllc~rhonvll-rl-methionine~ trifllloro~cet~te (1:2) s~lt A. (S)-1,3,4,9-Tetrahydro-2H-pyrido[3, 4 -b]indole-2,3-dicar~oxylic acid, 2-(1,1-~imethvlethvl) e~ter To a solution o~ (s)-2~3~4~9-Tetrahydro-l~-pyrido[ 3, 4 -b]indole-3-car~oxylic acid (2.4 g, 11.1 mmol) in lithium hydroxide (lN, 11.1 mL, deoxygenated) was ~e~ tetrahydro~uran (10 mLJ and Boc-anhydride (2.g g, 13.3 mmol). After 30 minutes, a small amount of precipitate formed.
Water and tetrahydrofuran (10 mL each) were added and stirred vigorously. After 2.5 hours, lN
hydrochloric acid (12 mL) was added and the mixture - was extracted with ethyl acetate (20 mL). The organic layer was dried (magnesium sul~ate) and concentrated in vaCuo to afford Compound ~ (3.4 g, 97~).
~S (CI): (M+H)~ = 317.
s. (R~)-N-[[2-[(1,1-Dimethylethoxy)carbonyl]-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-3-vllc~rhon~ll-r-methionine meth~l ester To a solution of Compound A (1.6 g, 5.0 mmol) in dimethylformamide (lS mL) at room temperature under argon were added L-Methionine, methyl ester, hydrochloride (1.0 g, S.0 mmol) and diisopropylethyl~mine (2.65 mL, 15 mmol). The mixture was stirred overnight (16 hours). The reaction mixture became dark. The reaction mixture -21~3~88 was partitioned between ethyl acetate and lN
hydrochloric acid (25 mL each). The organic layer was separated, washed with saturated sodium bicarbonate and 10% lithium chloride (20 mL each), dried (magnesium sulfate) ~nd concentrated in vacuo. The residue was purified by silica gel co~umn chromatography eluting with step gradient o~
25, 35 and 50% ethyl acetate in hexanes to afford Compound B (980 mg, ~2%).
MS (CI): (M+H)~= 461.
TLC: Rf 0.27 (1:1 ethyl aceta~e:hexanes, visualized by U.V. Ceric ammon. molybdate) C. (R~)-N-[[2,3,4,9-~etrahydro-lH-pyrido[3,4-b~indol-3-yl]-carbonyl]-L-methionine, methyl ester. trifll~oro~cet~te s~lt To a solution of Compound B (0.2 g, 0.43 mmol) in dichloromethane (1 mL) at room temperature under argon were added dimethyl sulfide (0.4 mL), trifluoroacetic acid (0.1 mL) and triethylsilane (0.04 mL, 0.25 mmol). .~fter 3 hours, trifluoroacetic acid (0.25 mL) was added. .~fter an additional 2 hours, .he voiatiles were removed n vacuo and the residue was -riturated with ether (3 x 2 mL) and dried in vacuo to afford a reddish oil Compound C (220 mg, 100%).
Al~ernatively, Compound C was also prepared by treating the same amount of Compound B with 98%
formic acid overnight (16 hours) and exchanging the formate salt with TsOH salt tO afford Compound C
(219 mg, 100 %).
~14~588 D. (S*,R*)-N-[[2-[N-[2-[[(1,1-Dimethyl ethoxy~carbonyl]amino]-3-~(triphenylmethyl) thio]propyl]-~-valyl]-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-3-yl]carbonyl]-L-methi oni ne, meth~l e~t~r Compound D was prepared using the method described in Compound G o~ Example 1 ~except dimethylformamide was not used.] Thus, Compound 2C
(210 mg, 0.~ mmol) and (S~)-N-[2-[[(1,1-Dimethylethoxy~carbonyl]amino~-3-[(triphenylmethyl)thioipropyl]-T-valine (219 mg, 0.~ mmol) were converted to compound D (82 mg, 23%).
MS (FAB): (M~H)' = 8g2.
TLC: R~ 0.21 (1:1 ethyl acetate:hexanes, visualized by U.V., Ceric ammon. molybdate).
Compound D was also prepared on the same scale using TsOH salt (81 mg, 23%). Both the batches were combined and used in the next step.
E. (S~,R*)-N-~[2-[N-(2-Amino-3-mercaptopropyl)-L-~alyl]-2,3,4,9-te~rahydro-lH-pyrido[3,4-b3indol-3-yl]carbonyl]-L-methionine, trifluoroacetate ~ ) s~lt The title compound was prepared using ~he two step procedure described in Example lH ~except that in the first step sodium hydroxide was used in place of lithium hydroxide and the reaction mixture was stirred for 1.5 hours and in the second step 1.2 equivalents instead of 2.0 equivalents of triethylsilane was used.] Thus, Compound D (160 mg, 0.18 mmol) was converted to the title compound (60 mg, 42%).
MS (FAB): (M~H)+ = 536.
2~3~8 m.p. 110-115C.
[a]D = + 18.9~ (c = 0.23, methanol).
IR (KBr): 2974, 1676, 1437, 1204 cm~l.
HPLC: YMC, S3, C18 (6 x 150 mm3 column, 220 ~m, 1.5 mL/minute: 10-90% a~ueous methanol with 0.2%
phosphoric acid, linear gradient o~er 30 minutes.
Retention time : 19.9 minutes.
Elemental analysis for C25H37N5O4S2~ 1.3 H2O .
2.1 TFA
C H N
Calculated 43.92 5.26 8.77 Found 44.12 5.04 8.42 lH NMR (CDCl3, with 5% CD30D, 270 MHz): d 7.49 (lH, d, J=7.8 Hz~, 7.33 (lH, d, 7.8 Hz), 7.16-7.09 (2 H, 1~ m), 5.15 (lH, d, J-16 Hz~, 5.04 (lH, d, J= 4 Hz), 4.6 (lH, d, J=16 Hz~, 4.35 (lH, m), 4.09 (lH, d, J=
S Hz), 3.3-2.82 (7H, m), 2.3-1.8 (5H, m), 1.95 and 1.68 (3H, tWO S), 1.18-1.03 (6H, m).
Chem., ~, 3110 (1990); ~ J is NR4, and the bond between K and L form one side of a fused phenyl ring, see D. G. Harvev, ~t ai., J. Chem Soc., i53 (1941) and A. srossi, et al., ~. Med. Chem. 16, 418, (1973); 5) J and L are NR4, and K is CR5, see M.
Cain, et al . , Heterocv~les, 19, 1003 (1982); and 6) J is O, and the bond between K and L form one side of a fused phenyl ring, see S. ueki, e~ al ., U. S .
Patent ~Jo. 5,126,448 issued June 30, 1992.
A compound of formula v can be treated with a suitable N-deprotecting agent to proviàe the corresponding free amine of formula VI:
~ 2143588 VI
J ~ L
N~CO~Pro-O A
(The prol and pro2 protecting groups are chosen so that prol can be selectively remo~ed in the presence of Pro2).
An amine of formula VI can be coupled with a suitable amine-protected amino acid of formula VII
(wherein Pro3 is an amine protecting group~:
VII Al P ' OH
R ¦ ¦
R~ O
using an approprla~e coupling reagent (e.g., 30P-Cl) to form a compouna of formula VIII:
VIII
J ~ L
AL ~ > H
Pro ~ ~ N ~ N ~ C02Pro (Compounds of formula VII are known in ~he art.
See, for exampLe, R.M. '.~illiams, ~Synthesis of -21435~8 L~69 Optically Active a-Amino Acids,~ Pergamon Press, Oxford, 1989).
Compounds of formula VIII can also be prepared by coupling a C-terminal protected amino acid of the formula IX (wherein Pro4 is a carboxylic acid protecting group):
IX
\~ O~L
R~
N ~ OPro4 with an amine-protected amino acid of formula VII
above to provide a compound of formula X:
J O L
A~ ~
Pro ~ N ~ ~ ~ OPro4 IL R2 ll R o o The Pro~ protecting group o~ compound x can be selectively removed by me~hods known in the art to provide a compound o~ formula XI below:
~ 21~3~8 XI
Pro~ ~ OH
(The Pro3 and Pro4 protecting groups are chosen so that Pro4 can be selectively removed in the presence of Pro3).
Coupling of a compound of formula XI with an amino ester of formula IV would then pro~ide compound VIII.
A compound of formula VIII can be selectively N-deprotected by methods known in the art to pro~ide an amine of formula XII:
XII
2,.1R~
H~ ~ N ~ N ~ CO2Pro (The pro2 and Pro3 protecting groups are chosen so that Pro3 can be selectively removed in the presence of Pro2).
Coupling of an amine of formula XII with an acid of formula XIII (wherein X is optionally protected and Pro5 is a thiol protecting group such as trityl):
~ 2143588 XIII
H (X~ l~
`f OH
( CH2 ) p ProsS
with a suitable coupling agent provides a compound 5 of formula xrv XIV
H(X~
~cyl~ R o O
Pro5S
3eprotection o~ the pro2 and ProS groups of XIV, and removal of the optionai protecting group on X, then provides a compound of formula I where Y
and Z are -C(O)-. (See T.W. Greene and P.G.M.
wuts, ~Protective Groups in Organic Synthesis", John Wiley & Sons, New York, l99l, for exemplary protectins groups for X, their formation and removal).
Alternatively, removal of the nitrogen protecting group (Pro3) from a compound of formula X gives an amine of formula XV:
2~13S88 XV
R O O
which can then be coupled with an acid of formula XIII to pro~ide a compound of formula XVI wherein X
is optionally protected:
XVI
J O L
H(X~
~ I ~ ~
( CH2 ) p O
Pro S
Selective deprotection o~ the Pro~ protecting group of XVI provides an acid of formula XVII:
XVII
.~3 H(XJ~ >
(CH2)p R O O
Pro'S
which can be coupled with an amine of formula IV to pro~ide a compound of formula XIV. Deprotection of the pro2 protecting group of XIV, and removal of the optional protecting group on X, then also provides a compound of formula I where Y and Z are --C ~O) --.
Further, a compound of formula I where Y and Z are -C(O)- can be prepared by automated solid phase peptide synthesis using methods that are well known in the art. See, for example:
a) M. Bodansky and A. Bodansky, ~The Practice of Peptide Synthesis~, springer-Verlag, Berlin/Heidelberg/New York/Tokyo, 1984i and b) J. M. Stewart and J. D. Young, "Solid Phase Peptide Synthesis~, Pierce C~emical Co., Rockport, Illinois, 1984.
In another process, an amino acid of formula VII (wherein Pro3 is a suitable amino protecting group) can be con~erted to the N-methoxy-N-methylamide of formula XVIII by methods known inthe art:
XVIII
Al fH3 Pro ~ N~ ~ C~ ~
Rl o A compound of formula XVIII can be reduced tO
an aldehyde of formula XIX by methods known in the art. (See, e.g., Fehrentz, et al ., Svnthe~is, ~76 (1983)):
- - -21435~8 XIX
Al Pro3~ ~CI~ ~ H
R' O
Alternatively, a compound of formula XIX can be prepared by reduction of a compound of formula VII with a reducing agent such as borane, followed by oxidation of the resulting alcohol using, for examp7e, the Swern method of oxidation. (See, e.g., Luly, et al., J. Or~. Ch~m., 52, 1487 (1987);
or Stanfield, et al., J. Or~. Chem~ 4~, 4797 (1981)). In yet another alternati~e, a compound of formula XIX can be prepared by reduction of an ester of a compound of formula VII with a reducing agent such as diisobu~ylaluminum hydride. See, e.g., Rich, et al ., ~ . Ora . Chem., 43, 3624 ( 1978).
An N-protected aldehyde of formula XIX can be reductiveLy aminated with an amine of formula VI to form a compound of formula xX using methods ~nown in the art (e.g., sorch, et al., ~. ~. Ch~. coc , ~, 2897 (1971)):
XX' ALR~
L~H
~ 2~3588 LD~9 A compound of formula XX can be treated with a suitable N-deprotecting agent to provide the corresponding free amine of formula XXI:
XXI
",i ~
R H O
(The pro2 and Pro3 protecting groups are chosen so that Pro3 can be selectively removed in the presence of Pro2).
A compound of formula XXI can be coupled with an acid of formula XXII (wherein X is optionally protected) using an appropriate coupling reagent tO
form a compound of formula XXII:
XXII
~(L
Pross Deprotection of the pro2 group of the compound of formula XXII, and removal of the optional protecting group on X, provides a compound of formula I where Y is -CtO~-, Z is -CH2-.
21~3~8 An acid of formula XIII (wherein X is optionally protected) can also be converted to the N-methoxy-N-methylamide of formula XXIII by methods known in the art (e.g., Fehrentz, et al ., Svnth~sis, 676 (1983)):
XXIII
~C~
C N- O
/ \
(CH~)p Pro S
A compound of formula XXIII can be selectively reduced to an aldehyde of formula xxrv by methods known in the art (e.g., r ehrentz, et al ., Svnthesis, 676 (1983)):
XXIV
H(X)~
C~
I H
(C~,)p Pro~S
An aldehyàe of formula XXIV can be reductiveiy aminated with an amine of formula XII to form a compound of formula XXV using methods known in the art (e.g., ~orch, et al ., J . ~m . Chem. Soc., ~, 2897 (1971)):
~ 3 5 8 8 - 2~ -XXV
J ~ L
H(X) H H ~1 ~ ~ H
N ~ C02Pro2 / CH2)p O A~
Pro~S
Deprotection of the Pro2, and removal of the optional protecting group on X, provides a compound of formula I where Y is -CH2-, Z is -C(O)-.
Alternatively, reductive amination o~ a compound of formula XXVI where pro6 is a carboxyLic acid protecting group:
XXVI
.;~,1 H~ ~ oPro~
1~n R' O
with a compound o f f ormula XXIV provides a compound of formula XXVII:
XXVII
H(X)~ V
OPro~
I 1~ R
(CH2)p 0 /
Pro'S
Selective deprotection of the pro6 group provides a compound o f f ormula XXVIII:
~ 21~3588 XXVIII
H(X) ~.H
( CH2 ) p Pro5S
which, on coupling with a compound of formula VI
(using, for example, BOP-Cl) provides a compound of S formula XX~.
By combining the appropriate steps above, one skilled in the art can also prepare a compound of formula I where both Y and Z are -CH2--Side-chain protecting groups may be used in these processes with amino acids ha~ing reactive functionalities, such as hydroxyl, carboxyl, amino, mercapto, guanidino, ; mi ~olyl, indolyl and the like. The particular protecting groups used for any amino acid residues depend upon the sidechains to be protected and are generally known in the art.
Exemplary sidechain protecting groups incLude acetyl, benzoyi, benzyl, t-butyl and the ike for hydroxyl; cyclohexyl, benzyl, methyl, ethyl, t-butyl and the like for carboxyl; benzyl, 4-methylbenzyl, 4-methoxybenzyl, acetyl, acetamidomethyl, triphenylmethyl (trityl) and the like for mercapto; t-butoxycarbonyl (Boc), benzyloxylcarbonyl (Cbz), ~-~(9~-Fluoren-~-ylmethoxy)carbonyl] (Fmoc~, phthaloyl (Pht), p-toluenesul~onyl (Tos), trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl (Teoc) and the like for amino; 2,4-dinitrophenyl, benzyloxymethyl, Tos, Boc, trityl and the like for imidazolyl; formyl, Cbz, Teoc, 2,2,2-trichloroethyl carbamate (TROC) and the like for indolyl; and tosyl, nitro, bis(1-adamantyloxycarbonyl) and the like for guanidino.
Side-chain protecting groups may be removed, if desired, by, for example, treatment with one or more deprotecting agents in an inert solvent or solvent mixture. For examples of protec~ing groups and suitable deprotecting agents, see M. Bodansky and A. Bodansky, ~The Practice of Peptide SynthesisU, springer-Verlag~ Inc. ~1984); and T. W.
Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis~, Second Edition, John Wiley Sons, New York, 1991.
The invention will now be further described by the following working examples, which are preferred embodiments of the invention. All temperatures are in degrees Celsius (C) unless otherwise indicated.
Compounds exemplified herein, which comprise a basic moiety such as an amine or substituted amine, may exist as a salt of an organic or inorganic acid. This information is not necessarily explicitly described in all the examples, but would be understood by those skilled in the arc. These examples are illustrative rather than limiting.
~ ~143~88 ~mn le N-[[5-[N-[(R)-2-Amino-3-mercaptopropyl]-L-valyl]-4,S,6,7-tetrahydrothieno~3,2-cipyridin-6-yl]-c~rhonvll-r,-methionine, trifllloro~cetAte (1:1) sAlt A. N2-~(1,1-Dime~hylethoxy)car~onyl]-N-methoxy-N-methyl-S-(triphenylmethyl)-r.-cvStein~mi ~le N-Butyloxycarbonyl-S-trityl-L-Cysteine (20.0 g, 43.14 mmol), 1-ethyl-3-(3-dimethyl~mi~opropyL) car~odiimide-~Cl (8.3 g, ~3.1 mmol) and 1-hydroxybenzotriazole hydrate (5.8 g, 43.1 mmol) were dissolved in dimethyl~ormamide (100 mL). N,O-Dimethylhydroxylamine hydrochloride (4.91 g, 50.6 mmol) and N,N-diiso~oy~lethylamine (6.13 g, 8.3 mL, 47.5 mmol) were then added. The reaction mixture was stirred ~or 5 hours at room temperature, poured into water (50 mL) and 2~ extracted with e~hyl acetate (3 x 200 mL). The combined organic layers were washed with water (3 x 500 mL) and brine (200 mL), dried magnesium sulfate, concentrated and chromatographed (silica gel, eluting with 40% ethyl acetate, 60% hexane).
Fractions containing the proàuct were collected and concentrated to yield Compound A as a white solid (19.95 g, 92%) B. N-[(1,1-Dimethylethoxy)car~onyl]-S-(trinhenYImethvl)-r.-cysteinAl Lithium aluminum hydride in tetrahydro~uran (lM, 59.3 mL, 59.3 mmol) was added dropwise to a solution of Compound A (25 g, ~9.4 mmol) in diethyi ether (500 mL) at -lSC, while keeping the .
temperature below -14C. The reaction was stirred at -15C for 30 minutes, quenched slowly with potassium hydrogen sulfate (134.4 g, 99.8 mmol) in water (400 mL), warmed to room temperature, and stirred for 1 hour. The organic layer was separated and washed sequentially with 10%
potassium hydrogen sulfate (1 x 200 mL), lN
hydrochloric acid (1 x 200 mL) and 10% sodium bicarbonate (1 x 300 mL). The organic layer was dried (magnesium sulfate), filtered and concentrated under ~acuum to a~ford the aldehyde Compound B (20 g, 90%), which was used withou~
further purification.
mp: 48-54C
TLC: Rf : 0.80 (1/1 hexane/ethyl acetate, visualization by W) MS: (M-H)- 446 IR: (KBr), 1713 cm~1 [a]D = + 16.0, ( c = 1.19 methanol) C. (R)-N-[2-[(1,1-Dimethylethoxy)carbonyl]-3-[(triphenyimethyl)thio3propyl]-1-valine, meth~] ester Acetic acid (2.6 mL, 44.74 mmol) was added eo a solution of Compound B 120 g, 44.74 mmoL) and L-valine methyl ester HCl (9.0 g, 53.7 mmol) in methanoi (50 mL). The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (2.8 g, 44.74 mmol) in tetrahydrofuran (50 mL) was added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with sodium bicarbonate (3.75 g, 44.74 mmol) in water (20 mL) and concentrated ~ , _ , .
under vacuum. The residue was dissolved in 10%
sodium bicarbonate (10 m~) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 9:1 hexane/acetone) to afford Compound C (17.7 g, 70%).
D. (R)-N-[2-[(1,1-Dimethylethoxy)carbonyl~-3-o r (tri~hen~lmethvl)th;ol~ro~vll-1-v~line A solution of lithium hydroxide (lN, 7.2 mL, 7.2 mmoi) and Compound C (2.0 g, 3.6 mmol~ in 2/2/1 tetrahydrofuran/dioxane/methanol (10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, and diluted with water (50 mL) and lN hydrochloric acid (11.1 mL). The aqueous mixture was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried (magnesium sulfate), filtered, concentrated under vacuum, and used without further purification to afford Compound D (2.08 g, 100%) as a white soiid.
mp: 155-i66C
TLC: Rf = 0.45 (9/1/0.05 chloroform~methanol/acetic acid, visualization by W) MS: (M+H)+ 549 E. 5-[(1,1-Dimethylethoxy)carbonyl~-4,5,5,7-tetrahyarothieno[3,2-cipyridine-5-carboxylic ~ci~
To a suspension of 6-carboxy-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.9 g, 4.9 mmol;
for preparation, see J. P. Maffrand, U.S. Patent No. 4,147,,87 issued April 3, 179) in dioxane (7 .
~ 2~3S~8 mL) at 0C was added 1~ sodium hydroxide (5 mL, 10 mmol) and water (5 mL). To the resulting clear solution was aàded soc-anhydride (1.53 g, 7.0 mmol) and the cold bath was removed. ~fter 1 hour, the reaction mixture was concentrated to hal~ the ~olume, and ethyl acetate (15 mL) and lN
hydrochloric acid (8 mL) were added with vigorou;s stirring. The aqueous layer was separated and extracted with ethyl acetate (10 mL). The organic layers were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to afford Compound E (i.52 g, 110% of theoretical).
~S (FAB), (M+H)+ = 284' lS F. N-[tS-[(1,1-Dimethylethoxy)carbon~l]-4,5,6,~-tetrahydrothieno~3,2-c~pyridin-6-vllc~rhon~ll-r-methionine methvl ester To a solution of Compound E (1.52 g) in dichloromethane (lS mL) at O~C under argon was added sequentially benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophospnate (2.21 g, ~.0 mmol), N-methylmorpholine (2.1 mL, 1 mmol) and the hydrochloride salt of L-me~hionine methyl ester (1.O g, S mmol). The reaction was allowed to warm to room temperature. ~fter 16 hours, the reaction mixture was washed successively with lN hydrochloric acid, saturated sodium bicarbonate and brine (lS mL each). Each aqueous layer was extracted separately with chloroform (10 mL). The organic layers were com~ined, dried (magnesium sulfate), iltered and concentrated.
The residue was purified by flash silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford Compound F (1.15 g).
2143~88 MS (CI), (M+H)+ = 429+
TLC : Rf 0.46 (50%, ethyl acetate in hexanes, visualized by W and ceric ammon. moiybdate) HPLC: YMC, S3, C18 (6 x 150 mm) column, 220 nm, 1.5 S mL/min: 0-90% aqueous methanol with 0.2% phosphoric acid, gradient over 30 minutes : Retention time :
28.2 and 28.3 minutes (two diastereomers) G. N-[[5-[N-[(R)-2-[(1,1-Dimethylethoxy)-carbonyl]-3-[(triphenylmethyl)thio]propyl]-L-valyl]-4,5,6,7-tetrahydrothieno[3,2-c~pyridin-6-yl]carbonyl]-~-methionine, methvl ester Anhydrous hydrochloric acid (4M in dioxane, 1~ 3 mL, 12 mmol) and triethylsilane (0.4 mL, 2.5 mmol) were added to Compound F (1.1 g, 2 57 mmol) at room temperature under argon. After stirring 1.5 hours, the volatiles were removed in vacuo and the residue was triturated with ether and dried in vacuo (1.0 g).
To the resulting amine hydrochloride (0.8 g) in dichloromethane (8 ~L) at 0C under argon was added the acid Compound D (1.0 g, 1.82 m~ol) and dimethylformamide (1 mL) to obtain a homogeneous 2~ solution. soP-cl (0.48 g, 1.9 mmol) and N,N-diisopropylethylamine (0.73 mL, 4.1 mmol) were added and the reaction mixture was stirred overnight at 5C. The reaction mixture was diluted with ethyl acetate (15 mL~ and washed sequentially with lN hydrogen chloride, saturated sodium bicar~onate and brine (10 mL eacA). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo . The r~sidue was purified by flash silica gel column c~romatography eluting with , ~ 2143~8 step gradient of 30%. 40% and 50~ ethyl acetate in hexanes to afford Compound G (240 mg, 15~), as a white foam.
In a separate, small scale experiment, S dimethyiformamide was not used as co-solvent. In this case, the yield of Compound G was 40%.
MS: (FAB) ~M+H)+ = 859+
TLC : Rf 0.51 (1:1, ethyl acetate in hexanes, visualized by W and ceric ammon. molybdate, shows two diastereomers when spotted very dilute).
HPLC: YMC, S3, C18 (6 x lS0 mm) column, 220 nm, ~.5 mL/min: 0-90% aqueous methanoi with Q.2% phosphoric acid, gradient over 30 minutes : Retention time :
30.9 minu~es.
1~
H. N-[[5-[N-[tR)-2-Amino-3-mercaptopropyl]-~-~alyl]-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-6-yl]carbonyi]-L-methionine, triflllQro~cet~e (1:1) s~lt ~0 To a solution of compound 5 (0.22 g, 0.26 mmoi) in methanol (1 mL) and tetrahydrofuran (2 mL) at room tempera~ure was added a~ueous lN lithium hydroxide (0.3 mL, a . 3 mmol). ~ter 8 hours, 1~
hydrogen chloride (l mL~ was added and the mixture was ex~racted with ethyl acetate (5 mL). The organic layer was dried (magnesium sulfa~e), filtered and concentrated in ~acuo to afford a white soiid (240 mg; MS (M+H)+ = 845+).
To a solution of the above solid (230 mg) ~n dichloromethane (1.2 mL) at room tempera~ure under argon was added triethylsilane (0.08 mL, 0.48 mmol) and trifluoroacetic acid (1 mL). After 1.5 hours, the volatiles were removed in vacuo and the residue was dissolved in deoxygena~ed 40% aqueous methanol.
21~3588 The precipitate formed was filtered through nylon 0.45 ~ filter and the filtrate was purified by RPHPLC (YMC, S10, C18, 30 x 500 mm column) eluting with a linear gradient of ~2%-66% aqueous methanol cont~i~ing 0.1% trifluoroacetic acid over 1 hour.
Appropriate fractions were collected and concentrated in vacuo to remo~e methanol. The r~aining solution was lyophili~ed to obtain the title compound (150 mg, 80%), as a white lyophilate.
m.p. 64-66C
MS:(FAB); (M+H)' = 502' HPLC: YMC, S3, C18 (6 x 150 mm) column, 220 nm, 1.5 mL/min: 10-90% a~ueous methznol with 0.2%
phosphoric acid, gradient over 30 minutes :
Retention time : 16.0 minutes [a~D = -16.2 (c= 0.6, methanol) Elemental analysis for C21H34N4O452. 1.2 ~2 2.05 trifluoroacetic acid ~ E
Calculated: 39.77 5.11 7.39 12.69 ~ound: 39.72 5.15 7.47 15.46 21~35~8 ~x;lmn le 2 (S~,R*)-N-[[2-[N-(2-Amino-3-merCaptOy ~yl)-L-valyl]-2,3,4,9-tetrahydro-lH-pyrido~3,4-b]indol-3-vllc~rhonvll-rl-methionine~ trifllloro~cet~te (1:2) s~lt A. (S)-1,3,4,9-Tetrahydro-2H-pyrido[3, 4 -b]indole-2,3-dicar~oxylic acid, 2-(1,1-~imethvlethvl) e~ter To a solution o~ (s)-2~3~4~9-Tetrahydro-l~-pyrido[ 3, 4 -b]indole-3-car~oxylic acid (2.4 g, 11.1 mmol) in lithium hydroxide (lN, 11.1 mL, deoxygenated) was ~e~ tetrahydro~uran (10 mLJ and Boc-anhydride (2.g g, 13.3 mmol). After 30 minutes, a small amount of precipitate formed.
Water and tetrahydrofuran (10 mL each) were added and stirred vigorously. After 2.5 hours, lN
hydrochloric acid (12 mL) was added and the mixture - was extracted with ethyl acetate (20 mL). The organic layer was dried (magnesium sul~ate) and concentrated in vaCuo to afford Compound ~ (3.4 g, 97~).
~S (CI): (M+H)~ = 317.
s. (R~)-N-[[2-[(1,1-Dimethylethoxy)carbonyl]-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-3-vllc~rhon~ll-r-methionine meth~l ester To a solution of Compound A (1.6 g, 5.0 mmol) in dimethylformamide (lS mL) at room temperature under argon were added L-Methionine, methyl ester, hydrochloride (1.0 g, S.0 mmol) and diisopropylethyl~mine (2.65 mL, 15 mmol). The mixture was stirred overnight (16 hours). The reaction mixture became dark. The reaction mixture -21~3~88 was partitioned between ethyl acetate and lN
hydrochloric acid (25 mL each). The organic layer was separated, washed with saturated sodium bicarbonate and 10% lithium chloride (20 mL each), dried (magnesium sulfate) ~nd concentrated in vacuo. The residue was purified by silica gel co~umn chromatography eluting with step gradient o~
25, 35 and 50% ethyl acetate in hexanes to afford Compound B (980 mg, ~2%).
MS (CI): (M+H)~= 461.
TLC: Rf 0.27 (1:1 ethyl aceta~e:hexanes, visualized by U.V. Ceric ammon. molybdate) C. (R~)-N-[[2,3,4,9-~etrahydro-lH-pyrido[3,4-b~indol-3-yl]-carbonyl]-L-methionine, methyl ester. trifll~oro~cet~te s~lt To a solution of Compound B (0.2 g, 0.43 mmol) in dichloromethane (1 mL) at room temperature under argon were added dimethyl sulfide (0.4 mL), trifluoroacetic acid (0.1 mL) and triethylsilane (0.04 mL, 0.25 mmol). .~fter 3 hours, trifluoroacetic acid (0.25 mL) was added. .~fter an additional 2 hours, .he voiatiles were removed n vacuo and the residue was -riturated with ether (3 x 2 mL) and dried in vacuo to afford a reddish oil Compound C (220 mg, 100%).
Al~ernatively, Compound C was also prepared by treating the same amount of Compound B with 98%
formic acid overnight (16 hours) and exchanging the formate salt with TsOH salt tO afford Compound C
(219 mg, 100 %).
~14~588 D. (S*,R*)-N-[[2-[N-[2-[[(1,1-Dimethyl ethoxy~carbonyl]amino]-3-~(triphenylmethyl) thio]propyl]-~-valyl]-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-3-yl]carbonyl]-L-methi oni ne, meth~l e~t~r Compound D was prepared using the method described in Compound G o~ Example 1 ~except dimethylformamide was not used.] Thus, Compound 2C
(210 mg, 0.~ mmol) and (S~)-N-[2-[[(1,1-Dimethylethoxy~carbonyl]amino~-3-[(triphenylmethyl)thioipropyl]-T-valine (219 mg, 0.~ mmol) were converted to compound D (82 mg, 23%).
MS (FAB): (M~H)' = 8g2.
TLC: R~ 0.21 (1:1 ethyl acetate:hexanes, visualized by U.V., Ceric ammon. molybdate).
Compound D was also prepared on the same scale using TsOH salt (81 mg, 23%). Both the batches were combined and used in the next step.
E. (S~,R*)-N-~[2-[N-(2-Amino-3-mercaptopropyl)-L-~alyl]-2,3,4,9-te~rahydro-lH-pyrido[3,4-b3indol-3-yl]carbonyl]-L-methionine, trifluoroacetate ~ ) s~lt The title compound was prepared using ~he two step procedure described in Example lH ~except that in the first step sodium hydroxide was used in place of lithium hydroxide and the reaction mixture was stirred for 1.5 hours and in the second step 1.2 equivalents instead of 2.0 equivalents of triethylsilane was used.] Thus, Compound D (160 mg, 0.18 mmol) was converted to the title compound (60 mg, 42%).
MS (FAB): (M~H)+ = 536.
2~3~8 m.p. 110-115C.
[a]D = + 18.9~ (c = 0.23, methanol).
IR (KBr): 2974, 1676, 1437, 1204 cm~l.
HPLC: YMC, S3, C18 (6 x 150 mm3 column, 220 ~m, 1.5 mL/minute: 10-90% a~ueous methanol with 0.2%
phosphoric acid, linear gradient o~er 30 minutes.
Retention time : 19.9 minutes.
Elemental analysis for C25H37N5O4S2~ 1.3 H2O .
2.1 TFA
C H N
Calculated 43.92 5.26 8.77 Found 44.12 5.04 8.42 lH NMR (CDCl3, with 5% CD30D, 270 MHz): d 7.49 (lH, d, J=7.8 Hz~, 7.33 (lH, d, 7.8 Hz), 7.16-7.09 (2 H, 1~ m), 5.15 (lH, d, J-16 Hz~, 5.04 (lH, d, J= 4 Hz), 4.6 (lH, d, J=16 Hz~, 4.35 (lH, m), 4.09 (lH, d, J=
S Hz), 3.3-2.82 (7H, m), 2.3-1.8 (5H, m), 1.95 and 1.68 (3H, tWO S), 1.18-1.03 (6H, m).
Claims (16)
1. A compound of the formula I
or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
A1 and A2 are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl;
Y and Z are each independently -CH2- or -C(O)-;
R1 and R2 are each independently H or alkyl;
R1 and A1 taken together may be -(CH2)m-;
R3 is H, alkyl or phenyl;
J, K and L are each independently, N, NR4, O, S or CR5 with the provisos that only one of the groups J, K and L can be O or S, one or two of the groups J, K and L may be N or NR4, and at least one of the groups J or L must be N, NR4, O or S to form a fused five-membered heteroring;
the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring;
X is O or NR6;
R4 is H, alkyl or phenylalkyl;
R5 is H or alkyl;
R6 is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R7;
R7 is H, alkyl, phenyl or substituted phenyl;
m is 3 or 4;
p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.
or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
A1 and A2 are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl;
Y and Z are each independently -CH2- or -C(O)-;
R1 and R2 are each independently H or alkyl;
R1 and A1 taken together may be -(CH2)m-;
R3 is H, alkyl or phenyl;
J, K and L are each independently, N, NR4, O, S or CR5 with the provisos that only one of the groups J, K and L can be O or S, one or two of the groups J, K and L may be N or NR4, and at least one of the groups J or L must be N, NR4, O or S to form a fused five-membered heteroring;
the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring;
X is O or NR6;
R4 is H, alkyl or phenylalkyl;
R5 is H or alkyl;
R6 is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R7;
R7 is H, alkyl, phenyl or substituted phenyl;
m is 3 or 4;
p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.
2. A compound of Claim 1, wherein A1 is H or D-, L- or DL- -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2CH2NH2, -CH2C(O)OH, -CH2CH2C(O)OH, -CH2C(O)NH2, , , -CH2CH3, -CH2CH2C(O)NR10R11 where R10 and R11 are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6, -CH2CH2OCH3, -CH2CH2C(O)NHOH, -CH2SH, -CH2CH2SH, -CH2CH2S(O)2NH2 or -CH2CH2SCH3.
3. A compound of Claim 1, wherein A2 is H or D-, L- or DL- -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, , -CH2CH2CH2OH, -CH(OH)CH3, , , -CH2CH2CH2CH2NH2, , -CH2C(O)OH, -CH2CH2C(O)OH, -CH2C(O)NH2 , , , -CH2CH3, -CH2CH2C(O)NR10R11 where R10 and R11 are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6, -CH2CH2OCH3, -CH2CH2C(O)NHOH, -CH2SH, -CH2CH2SH, -CH2CH2S(O)2NH2 or -CH2CH2SCH3.
4. A compound of Claim 1, wherein A1 and A2 are each independently H or D-, L- or DL- -CH3, -CH(CH)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, C(CH3)3, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH3, , , , , CH2CH2CH2CH2NH2, -CH2C(O)OH, -CH2CH2C(O)OH, -CH2C(O)NH2, , , -CH2CH3, -CH2CH2C(O)NR10R11 where R10 and R11 are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6, -CH2CH2OCH3, -CH2CH2C(O)NHOH, -CH2SH, -CH2CH2SH, -CH2CH2S(O)2NH2 or -CH2CH2SCH3.
5. A compound of Claim 1, wherein A1 is L--CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CH2OH or -CH(OH)CH3.
6. A compound of Claim 1, wherein A2 is L--CH2CH2SCH3, -CH2CH2OH, -CH2CH2CH2OH , -CH2CH2C(O)NR10R11 where R10 and R11 are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6 or -CH2CH2OCH3.
7. A compound of Claim 1, wherein the fused five-membered optionally substituted heteroring is , , , , , or .
8. A compound of Claim 1, wherein X is NR6.
9. A compound of Claim 1, wherein R1, R2, R3, R4, R6 and R7 are H.
10. A compound of Claim 1, wherein A1 is L--CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CH2OH or -CH(OH)CH3; A2 is L--CH2CH2SCH3, -CH2CH2OH , -CH2CH2CH2OH, -CH2CH2C(O)NR10R11 where R10 and R11 are each, independently, H, alkyl, phenyl or phenylalkyl, or R10 and R11 taken together are (-CH2)t- where t is an integer from 2 to 6, or -CH2CH2OCH3; the fused five-membered optionally substituted heteroring is , , , , , or ;
X is NR6; R1, R2, R3, R4, R6 and R7 are H; and p is 1.
X is NR6; R1, R2, R3, R4, R6 and R7 are H; and p is 1.
11. A compound of Claim 1, selected from the group consisting of:
N-[[5-[N-[(R)-2-Amino-3-mercaptopropyl]-L-valyl]-4,5,6,7-tetrahydrothieno[3,2c]-pyridin-6-yl]-carbonyl]-L-methionine and (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl]carbonyl]-L-methionine.
N-[[5-[N-[(R)-2-Amino-3-mercaptopropyl]-L-valyl]-4,5,6,7-tetrahydrothieno[3,2c]-pyridin-6-yl]-carbonyl]-L-methionine and (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl]carbonyl]-L-methionine.
12. A method of inhibiting farnesyl protein transferase which comprises administering to a mammalian subject an effective farnesyl protein transferase inhibiting amount of a compound of Claim 1.
13 . A method of inhibiting prenyl transferases which comprises administering to a mammalian subject an effective prenyl transferase inhibiting amount of a compound of Claim 1.
14 . A method of inhibiting tumors which comprises administering to a mammalian subject an effective tumor inhibiting amount of a compound of Claim 1.
15. A method of treating diseases associated with signal transduction pathways operating through Ras which comprises administering to a mammalian subject an amount of a compound of Claim 1 effective for treating said diseases.
16. A method of treating diseases associated with proteins that are post-translationally modified by the enzyme farnesyl protein transferase which comprises administering to mammalian subject an amount of a compound of Claim 1 effective for treating said diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21753794A | 1994-03-24 | 1994-03-24 | |
| US217,537 | 1994-03-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2143588A1 true CA2143588A1 (en) | 1995-09-25 |
Family
ID=22811478
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002143588A Abandoned CA2143588A1 (en) | 1994-03-24 | 1995-02-28 | Inhibitors of farnesyl protein transferase |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2143588A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6271197B1 (en) | 1996-04-11 | 2001-08-07 | Gpc-Biotech Inc. | Assays and reagents for identifying anti-fungal agents, and uses related thereto |
| US6455281B1 (en) | 1996-04-11 | 2002-09-24 | Gpc Biotech Inc. | Nucleic acids for identifying anti-fungal agents, and uses related thereto |
| US6696280B2 (en) | 1996-04-11 | 2004-02-24 | Gpc Biotech, Inc. | Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto |
| CN114591323A (en) * | 2022-03-17 | 2022-06-07 | 济南大学 | Hydroxamic acid histone deacetylase inhibitor containing tetrahydrocarboline structure and preparation method and application thereof |
-
1995
- 1995-02-28 CA CA002143588A patent/CA2143588A1/en not_active Abandoned
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6271197B1 (en) | 1996-04-11 | 2001-08-07 | Gpc-Biotech Inc. | Assays and reagents for identifying anti-fungal agents, and uses related thereto |
| US6277564B1 (en) | 1996-04-11 | 2001-08-21 | Gpc Biotech Inc. | Assays and reagents for identifying anti-fungal agents, and uses related thereto |
| US6455281B1 (en) | 1996-04-11 | 2002-09-24 | Gpc Biotech Inc. | Nucleic acids for identifying anti-fungal agents, and uses related thereto |
| US6696280B2 (en) | 1996-04-11 | 2004-02-24 | Gpc Biotech, Inc. | Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto |
| US6727082B1 (en) | 1996-04-11 | 2004-04-27 | Gpc Biotech Inc. | Assays and reagents for identifying anti-fungal agents, and uses related thereto |
| CN114591323A (en) * | 2022-03-17 | 2022-06-07 | 济南大学 | Hydroxamic acid histone deacetylase inhibitor containing tetrahydrocarboline structure and preparation method and application thereof |
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Effective date: 20110228 |