U.S. patent application number 10/600303 was filed with the patent office on 2004-12-30 for cyclosporin derivatives for the treatment of immune disorders.
Invention is credited to Or, Yat Sun, Wu, Frank X. H..
Application Number | 20040266669 10/600303 |
Document ID | / |
Family ID | 33539414 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040266669 |
Kind Code |
A1 |
Wu, Frank X. H. ; et
al. |
December 30, 2004 |
Cyclosporin derivatives for the treatment of immune disorders
Abstract
The present invention relates to a cyclosporin analog of the
following formula (I) or a pro-drug or pharmaceutically acceptable
salt thereof: 1 wherein A is of the formula: 2 where Q, W, X, Y,
and Z are defined herein. In a second embodiment, the present
invention relates to pharmaceutical compositions comprising
pro-drugs or pharmaceutically acceptable salts of the compounds of
the present invention and the use thereof for treating autoimmune
diseases or for the prevention of organ transplantation rejection
in a subject. In a third embodiment, the present invention relates
to processes for the production of novel cyclosporin analogs of the
present invention.
Inventors: |
Wu, Frank X. H.;
(Shrewsbury, MA) ; Or, Yat Sun; (Watertown,
MA) |
Correspondence
Address: |
EDWARDS & ANGELL, LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Family ID: |
33539414 |
Appl. No.: |
10/600303 |
Filed: |
June 20, 2003 |
Current U.S.
Class: |
514/1.7 ;
514/1.8; 514/20.5; 530/321 |
Current CPC
Class: |
C07K 7/645 20130101;
A61P 43/00 20180101; A61K 38/13 20130101 |
Class at
Publication: |
514/011 ;
530/321 |
International
Class: |
A61K 038/13; C07K
007/64 |
Claims
What is claimed is:
1. A cyclosporin analog of formula I or a pro-drug or a
pharmaceutically acceptable salt thereof:
2 74
and A is of the formula: 75wherein: Q is 76where i) X is selected
from hydrogen, halogen, C.sub.1-C.sub.6 alkyl, or aryl; ii) one of
Y and Z is selected from: hydrogen, deuterium, halogen, or methyl
and the other is independently selected from: a) halogen; b)
R.sub.1, where R.sub.1 is selected from: 1) hydrogen; 2) deuterium;
3) C.sub.1-C.sub.6 alkyl, optionally substituted with halogen, TMS,
aryl, heterocycloalkyl, or heteroaryl; 4) C.sub.2-C.sub.6 alkenyl,
optionally substituted with halogen, TMS, aryl, heterocycloalkyl,
or heteroaryl; 5) C.sub.2-C.sub.6 alkynyl, optionally substituted
with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl; 6)
C.sub.3-C.sub.12 cycloalkyl; 7) substituted C.sub.3-C.sub.12
cycloalkyl; 8) aryl; 9) substituted aryl; 10)heterocycloalkyl;
11)substituted heterocycloalkyl; 12)heteroaryl; or 13)substituted
heteroaryl; c) --C(O)OR.sub.1, where R.sub.1 is as previously
defined; d) --C(O)OCH.sub.2--V--R.sub.1, where R.sub.1 is as
previously defined and V is --O-- or --S--; e)
--C(O)N(R.sub.3)(R.sub.4), where R.sub.3 and R.sub.4 are
independently selected from R.sub.1 as previously defined; f)
--C(O)SR.sub.1, where R.sub.1 is as previously defined; g)
--C(O)OCH.sub.2OC(O)R.sub.1, where R.sub.1 is as previously
defined; h) --C(S)OR.sub.1, where R.sub.1 is as previously defined;
i) --C(S)SR.sub.1, where R.sub.1 is as previously defined; j)
R.sub.2, where R.sub.2 is selected from: 1) C.sub.1-C.sub.6
alkyl-M-R.sub.1, where R.sub.1 is as previously defined and M is
absent or selected from: i. --NH--; ii. --N(CH.sub.3)--; iii.
--S--; iv. --S(O).sub.n--, where n=0, 1, or 2; or v. --O--; 2)
C.sub.2-C.sub.6 alkenyl-M-R.sub.1, where R.sub.1 and M are as
previously defined; or 3) C.sub.2-C.sub.6 alkynyl-M-R.sub.1, where
R.sub.1 and M are as previously defined; k) Or in the alternative,
Y and Z are taken together with the carbon atom to which they are
attached to form a C.sub.3-C.sub.12 cycloalkyl moiety; and iii) G
is independently selected from halogen, TMS, R.sub.1 or R.sub.2 as
previously defined; B is selected from: i) -.alpha.Abu-; ii) -Val-;
iii) -Thr-; or iv) -Nva-; U is selected from: i) -(D)Ala-; ii)
-(D)Ser-; iii) --[O-(2-hydroxyethyl)(D)Ser]-; iv)
--[O-(acyl)(D)Ser]-; or v) --[O-(2-acyloxyethyl)(D)Ser]-; and W is
selected from hydrogen or a hydroxy protecting group.
2. A compound formula I according to claim 1, wherein A is of the
formula A1: 77where W, X, Y, and Z are as previously defined.
3. A compound of formula I according to claim 1, wherein A is of
the formula A2: 78where X, Y, and Z are as previously defined.
4. A compound of formula I according to claim 1, wherein A is of
the formula A3: 79where Y and Z are as previously defined.
5. A compound of formula I according to claim 1, wherein A is of
the formula A4: 80where W and G are as previously defined.
6. A compound of formula I according to claim 1, wherein A is of
the formula A5: 81where G is as previously defined.
7. A compound of formula I, according to claim 1, selected from:
Example 1. A compound of formula I, wherin A is of the formula
(1-2) and W is Ac; Example 2. A compound of formula I, wherein Q is
82W is Ac and X.dbd.Y=Z=hydrogen; Example 3. A compound of formula
I, wherein Q is 83W is H and X.dbd.Y=Z=hydrogen; Example 4. A
compound of formula I, wherein Q is 84Y is CH.sub.3, and
W.dbd.X=Z=hydrogen; Example 5. A compound of formula I, wherein Q
is 85Y=Z=CH.sub.3, and W.dbd.X=hydrogen; Example 6. A compound of
formula I, wherein Q is 86Y is --(CH.sub.2).sub.3CH.sub.3, and
W.dbd.X=Z=hydrogen; Example 7. A compound of formula I, wherein Q
is 87Y is --(CH.sub.2).sub.2Br, and W.dbd.X=Z=hydrogen; Example 8.
A compound of formula I, wherein Q is 88Y is ortho-Me-phenyl, and
W.dbd.X=Z=hydrogen; Example 9. A compound of formula I, wherein Q
is 89Y is ortho-Br-phenyl, and W.dbd.X=Z=hydrogen; Example 10. A
compound of formula I, wherein Q is 90Y is --CO.sub.2Me, and
W.dbd.X=Z=hydrogen; Example 11. A compound of formula I, wherein Q
is 91Y is meta-CHO-phenyl, and W.dbd.X=Z=hydrogen; Example 12. A
compound of formula I, wherein Q is 92Y is Et, and
W.dbd.X=Z=hydrogen; Example 13. A compound of formula I, wherein Q
is 93Y is --CH.dbd.CHCH.sub.2TMS, and W.dbd.X=Z=hydrogen; Example
14. A compound of formula I, wherein Q is 94G is H, and W is H;
Example 15. A compound of formula I, wherein Q is 95Y is propyl,
and W.dbd.X=Z=hydrogen; Example 16. A compound of formula I,
wherein Q is 96Y is cyclopropyl, and W.dbd.X=Z=hydrogen; Example
17. A compound of formula I, wherein Q is 97Y is
--CH.dbd.CHCH.sub.3, and W.dbd.X=Z=hydrogen; Example 18. A compound
of formula I, wherein Q is 98X.dbd.Y.dbd.CH.sub.3, and
W=Z=hydrogen; Example 19. A compound of formula I, wherein Q is
99W.dbd.X.dbd.Y=hydrogen, and Z=CH.sub.3; Example 20. A compound of
formula I, wherein Q is 100Y is p-bromophenyl, and
W.dbd.X=Z=hydrogen; Example 21. A compound of formula I, wherein Q
is 101W.dbd.X.dbd.Y=hydrogen, and Z=--CH.sub.2CH.dbd.CH.sub.2;
Example 22. A compound of formula I, wherein Q is
102W.dbd.X.dbd.Y=hydrogen, and Z is ethyl; Example 23. A compound
of formula I, wherein Q is 103W.dbd.X.dbd.Y=hydrogen, and
Z=--CH.dbd.CHCH.sub.3; Example 24. A compound of formula I, wherein
Q is 104W.dbd.X.dbd.Y=hydrogen, and Z=--CH.sub.2OCH.sub.3; Example
25. A compound of formula I, wherein Q is 105G=--CH.dbd.CHCH.sub.3
and W=hydrogen; Example 26. A compound of formula I, wherein Q is
106G=propyl and W=hydrogen; or Example 27. A compound of formula I,
wherein Q is 107G=--CH.sub.3 and W=hydrogen.
8. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of Formula (I) in claim
1, or a pharmaceutically acceptable salt, ester or prodrug thereof,
in combination with a pharmaceutically acceptable carrier or
excipient.
9. A method of treating organ transplantation rejection in a
subject, which comprises administering to said subject a
therapeutically effective amount of the pharmaceutical composition
of claim 8.
10. A method of treating an immune disorder in a subject, which
comprises administering to said subject a therapeutically effective
amount of the pharmaceutical composition of claim 1.
11. The method of claim 10, wherein said immune disorder is
selected from the group consisting of: rheumatoid arthritis,
inflammatory bowel disease, psoriasis, asthma, atopic dermatitis,
allergic rhinitis, and chronic obstructive pulmonary disease.
12. A method of treating an immune disorder in a subject, which
comprises topically administering to said subject a therapeutically
effective amount of the pharmaceutical composition of claim 1.
13. The method of claim 12, wherein said inflammatory or immune
disorder is selected from the group consisting of psoriasis and
eczema.
14. The method of claim 12, wherein said topically administering is
achieved via inhalation.
15. The method of claim 14, wherein said inflammatory or immune
disorder is an obstructive airways disease.
16. The method of claim 15, wherein said airways disease is
selected from the group consisting of asthma, allergic rhinitis,
bronchitis, cystic fibrosis, and chronic obstructive pulmonary
disease.
17. The method of claim 16, wherein said chronic obstructive
pulmonary disease is emphysema or chronic bronchitis.
18. A process for the preparation of a compound of formula I,
wherein Q is z 108wherein X, Y, and Z are as defined in claim 1,
comprising i) reacting cyclosporin A with a reagent capable of
oxidative cleavage to form a compound of formula I, wherein A is
represented by the formula: 109where W is as defined in claim 1;
ii) reacting a compound formed in step i with a Grignard reagent of
formula 110where X, Y, and Z are as defined in claim 1 to form a
compound of formula I, wherein A is represented by the formula:
111wherein W, X, Y, and Z are as defined in claim 1; iii) reacting
a compound formed in step ii with an with an electrophile, such as,
but not limited to, mesyl chloride, chloroformate, or triflate
chloride to form a compound of formula I, wherein A is represented
by the formula: 112wherein EWG is an electron withdrawing group and
W, X, Y, and Z are as defined in claim 1; and iv) reacting a
compound formed in step iii with a palladium catalyst.
19. A process for the preparation of a compound of formula I,
wherein Q is 113comprising i) reacting a compound formed in step i
of claim 18 with a lithium acetylide represented by the formula
114wherein G is as defined in claim 1 to form a compound of
formula, wherein A is represented by the formula 115wherein G and W
are as defined in claim 1; ii) reacting a compound formed in step i
with an electrophile, such as, but not limited to, mesyl chloride,
chloroformate, or triflate chloride to form a compound of formula
I, wherein A is represented by the formula 116wherein EWG is an
electron-withdrawing group, and G and W are as defined in claim 1,
which then undergoes elimination.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel semisynthetic
cyclosporin analogs for the prevention of organ transplantation
rejection and the treatment of immune disorders and inflammation,
their use as pharmaceuticals and pharmaceutical compositions
comprising them, as well as the processes for their production.
BACKGROUND OF THE INVENTION
[0002] The cyclosporins comprise a class of structurally
distinctive, cyclic, poly-N-methylated undecapeptides, commonly
possessing pharmacological, in particular immunosuppressive,
anti-inflammatory and antiparasitic activity. The first of the
cyclosporins to be isolated was the naturally occurring fungal
metabolite Ciclosporin or Cyclosporin, also known as cyclosporin A.
3 4
[0003] Since the original discovery of Cyclosporin, a wide variety
of naturally occurring cyclosporins have been isolated and
identified, and many further non-natural cyclosporins have been
prepared by total- or semi-synthetic means or by the application of
modified culture techniques. The class comprised by the
cyclosporins is thus now substantial and includes, for example, the
naturally occurring cyclosporins A through Z [cf., Traber et al.;1,
Helv. Chim. Acta, 60, 1247-1255 (1977); Traber et al.; 2, Helv.
Chim. Acta, 65,1655-1667 (1982); Kobel et al.; Europ. J. Applied
Microbiology and Biotechnology, 14, 273-240 (1982); and von
Wartburg et al.; Progress in Allergy, 38, 28-45 (1986)], as well as
various non-natural cyclosporin derivatives and artificial or
synthetic cyclosporin derivatives and artificial or synthetic
cyclosporins including dihydrocyclosporins [in which the the
-MeBmt-residue is saturated by hydrogenation]; derivatized
cyclosporins (e.g., in which the 3'-O-atom of the -MeBmt- residue
is acylated or a further substituent is introduced at the
.alpha.-carbon atom of the sarcosyl residue at the 3-position); and
cyclosporins in which variant amino acids are incorporated at
specific positions within the peptide sequence, e.g. employing the
total synthetic method for the production of cyclosporins developed
by R. Wenger--see e.g. Traber et al., 1; Traber et al., 2; and
Kobel et al., loc cit. U.S. Pat. Nos. 4,108,985, 4,220,641,
4,288,431, 4,554,351, 4,396,542 and 4,798,823; European Patent
Publication Nos. 34,567A, 56,782A, 300,784A and 300,785;
International Patent Publication No. WO 86/02080 and UK Patent
Publication Nos. 2,206,119 and 2,207,678; Wenger 1, Transpl. Proc.,
15 Suppl. 1:2230 (1983); Wenger 2, Angew. Chem. Int. Ed. 24 77
(1985) and Wenger 3, Progress in the Chemistry of Organic Natural
Products, 50, 123 (1986).
[0004] Several synthetic modifications of the -MeBmt- residue
residing at position 1 of the cyclosporin undecapeptide have been
described including: Park et al., Tetrahedron Lett.1989, 30,
4215-4218; U.S. Pat. Nos. 5,239,037, 5,293,057; U.S. Publication
Nos. US20020142946, US20030087813, and US20030104992 assigned to
Enanta Pharmaceuticals, Inc.; PCT Publication Nos. WO99/18120 and
WO03/033526 both assigned to Isotechnika; and U.S. Pat. Nos.
4,384,996, 4,771,122, 5,284,826, and 5,525,590 assigned to
Sandoz.
[0005] The compound cyclosporine (cyclosporine A or CsA) has found
wide use since its introduction in the fields of organ
transplantation and immunomodulation, and has brought about a
significant increase in the success rate for transplantation
procedures. Undesired side effects associated with cyclosporine,
however, such as nephrotoxicity, have led to a continued search for
immunosuppressant compounds having improved, efficacy and
safety.
[0006] Side effects with systemic CsA include increase in diastolic
blood pressure and decrease in renal function. Other side effects
include hepatic dysfunction, hypertrichosis, tremor, gingival
hyperplasis and paraesthsia. The systemic toxicity of CsA limits
its use for the treatment of certain diseases. Accordingly, a need
exists for compounds which exhibit immunosuppressive activity while
not producing systemic toxicity.
SUMMARY OF THE INVENTION
[0007] The present invention relates to novel cyclosporin analogs
and methods of treatment for the prevention of organ
transplantation rejection and the treatment of immune disorders or
inflammation in a subject. The present invention further relates to
pharmaceutical compositions comprising the compounds of the present
invention and processes for their production.
[0008] More particularly, the present invention provides a
cyclosporin of the following Formula (I),
1 5
[0009] wherein
[0010] A is of the formula: 6
[0011] wherein:
[0012] Q is 7
[0013] where
[0014] i) X is selected from hydrogen, halogen, C.sub.1-C.sub.6
alkyl, or aryl;
[0015] ii) one of Y and Z is selected from: hydrogen, deuterium,
halogen, or methyl and the other is independently selected
from:
[0016] a) halogen;
[0017] b) R.sub.1, where R.sub.1 is selected from:
[0018] 1) hydrogen;
[0019] 2) deuterium;
[0020] 3) C.sub.1-C.sub.6 alkyl, optionally substituted with
halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
[0021] 4) C.sub.2-C.sub.6 alkenyl, optionally substituted with
halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
[0022] 5) C.sub.2-C.sub.6 alkynyl, optionally substituted with
halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
[0023] 6) C.sub.3-C.sub.12 cycloalkyl;
[0024] 7) substituted C.sub.3-C.sub.12 cycloalkyl;
[0025] 8) aryl;
[0026] 9) substituted aryl;
[0027] 10)heterocycloalkyl;
[0028] 11)substituted heterocycloalkyl;
[0029] 12)heteroaryl; or
[0030] 13)substituted heteroaryl;
[0031] c) --C(O)OR.sub.1, where R.sub.1 is as previously
defined;
[0032] d) --C(O)OCH.sub.2--V--R.sub.1, where R.sub.1 is as
previously defined and V is --O-- or --S--;
[0033] e) --C(O)N(R.sub.3)(R.sub.4), where R.sub.3 and R.sub.4 are
independently selected from R.sub.1 as previously defined;
[0034] f) --C(O)SR.sub.1, where R.sub.1 is as previously
defined;
[0035] g) --C(O)OCH.sub.2OC(O)R.sub.1, where R.sub.1 is as
previously defined;
[0036] h) --C(S)OR.sub.1, where R.sub.1 is as previously
defined;
[0037] i) --C(S)SR.sub.1, where R.sub.1 is as previously
defined;
[0038] j) R.sub.2, where R.sub.2 is selected from:
[0039] 1) C.sub.1-C.sub.6 alkyl-M-R.sub.1, where R.sub.1 is as
previously defined and M is absent or selected from:
[0040] i. --NH--;
[0041] ii. --N(CH.sub.3)--;
[0042] iii. --S--;
[0043] iv. --S(O).sub.n--, where n=0, 1, or 2; or
[0044] v. --O--;
[0045] 2) C.sub.2-C.sub.6 alkenyl-M-R.sub.1, where R.sub.1 and M
are as previously defined; or
[0046] 3) C.sub.2-C.sub.6 alkynyl-M-R.sub.1, where R.sub.1 and M
are as previously defined;
[0047] k) Or in the alternative, Y and Z are taken together with
the carbon atom to which they are attached to form a
C.sub.3-C.sub.12 cycloalkyl moiety; and
[0048] ii) G is independently selected from halogen, TMS, R.sub.1
or R.sub.2 as previously defined;
[0049] B is selected from:
[0050] i) -.alpha.Abu-;
[0051] ii) -Val-;
[0052] iii) -Thr-; or
[0053] iv) -Nva-;
[0054] U is selected from:
[0055] i) -(D)Ala-;
[0056] ii) -(D)Ser-;
[0057] iii) --[O-(2-hydroxyethyl)(D)Ser]-;
[0058] iv) --[O-(acyl)(D)Ser]-; or
[0059] v) --[O-(2-acyloxyethyl)(D)Ser]-; and
[0060] W is selected from hydrogen or a hydroxy protecting
group.
[0061] In Formula (I), amino acid residues referred to by
abbreviation, eg. -Ala-, -MeLeu-, -.alpha.Abu-, etc., are, in
accordance with conventional practice, to be understood as having
the L-configuration unless otherwise indicated. (For example,
-(D)Ala- represents a residue having the D-configuration). Residue
abbreviation preceeded by "Me" as in the case of "MeLeu,"
represents an .alpha.-N-methylated residue. Individual residues of
the cyclosporin molecule are numbered, as in the art, clockwise and
starting with the residue, -MeBmt- corresponding to residue 1. The
same numerical sequence is employed throughout the present
specifications and claims.
[0062] Accordingly, the present invention provides the use of
cyclosporin analogs for the treatment of, with or without the
concurrent use of other drugs, organ transplantation rejections,
immune disorders, and inflammation including, but not limited to,
indications such as rheumatoid arthritis, psoriasis, inflammatory
bowel diseases, chronic obstructive pulmonary disease, allergic
rhinitis, and asthma.
DETAILED DESCRIPTION OF THE INVENTION
[0063] A first embodiment of the invention is a compound
represented by Formula I as described above, or a pharmaceutically
acceptable salt, ester or prodrug thereof.
[0064] Representative subgenera of the present invention include,
but are not limited to, the following:
[0065] A compound of formula I: A is of the formula A1: 8
[0066] where W, X, Y, and Z are as previously defined;
[0067] A compound of formula I: A is of the formula A2: 9
[0068] where X, Y, and Z are as previously defined;
[0069] A compound of formula I: A is of the formula A3: 10
[0070] where Y and Z are as previously defined;
[0071] A compound of formula I: A is of the formula A4: 11
[0072] where W and G are as previously defined; or
[0073] A compound of formula I: A is of the formula A5: 12
[0074] G is as previously defined.
[0075] Representative compounds of the invention include, but are
not limited to, the compounds selected from:
[0076] Example 1. A compound of formula I, wherin A is of the
formula (1-2) and W is Ac;
[0077] Example 2. A compound of formula I, wherein Q is 13
[0078] W is Ac and X.dbd.Y=Z =hydrogen;
[0079] Example 3. A compound of formula I, wherein Q is 14
[0080] W is H and X.dbd.Y=Z =hydrogen;
[0081] Example 4. A compound of formula I, wherein Q is 15
[0082] Y is CH.sub.3, and W.dbd.X=Z=hydrogen;
[0083] Example 5. A compound of formula I, wherein Q is 16
[0084] Y.dbd.Z=CH.sub.3, and W=X=hydrogen;
[0085] Example 6. A compound of formula I, wherein Q is 17
[0086] Y is --(CH.sub.2).sub.3CH.sub.3, and W.dbd.X=Z=hydrogen;
[0087] Example 7. A compound of formula I, wherein Q is 18
[0088] Y is --(CH.sub.2).sub.2Br, and W.dbd.X=Z=hydrogen;
[0089] Example 8. A compound of formula I, wherein Q is 19
[0090] Y is ortho-Me-phenyl, and W.dbd.X=Z=hydrogen;
[0091] Example 9 A compound of formula I, wherein Q is 20
[0092] Y is ortho-Br-phenyl, and W.dbd.X=Z=hydrogen;
[0093] Example 10. A compound of formula I, wherein Q is 21
[0094] Y is --CO.sub.2Me, and W.dbd.X=Z=hydrogen;
[0095] Example 11. A compound of formula I, wherein Q is 22
[0096] Y is meta-CHO-phenyl, and W.dbd.X=Z=hydrogen;
[0097] Example 12. A compound of formula I, wherein Q is 23
[0098] Y is Et, and W.dbd.X=Z=hydrogen;
[0099] Example 13. A compound of formula I, wherein Q is 24
[0100] Y is --CH.dbd.CHCH.sub.2TMS, and W.dbd.X=Z=hydrogen;
[0101] Example 14. A compound of formula I, wherein Q is 25
[0102] G is H, and W is H.
[0103] Example 15. A compound of formula I, wherein Q is 26
[0104] Y is propyl, and W.dbd.X=Z=hydrogen.
[0105] Example 16. A compound of formula I, wherein Q is 27
[0106] Y is cyclopropyl, and W.dbd.X=Z=hydrogen.
[0107] Example 17. A compound of formula I, wherein Q is 28
[0108] Y is --CH.dbd.CHCH.sub.3, and W.dbd.X=Z=hydrogen.
[0109] Example 18. A compound of formula I, wherein Q is 29
[0110] X.dbd.Y.dbd.CH.sub.3, and W=Z=hydrogen.
[0111] Example 19. A compound of formula I, wherein Q is 30
[0112] W.dbd.X.dbd.Y=hydrogen, and Z=CH.sub.3.
[0113] Example 20. A compound of formula I, wherein Q is 31
[0114] Y is p-bromophenyl, and W.dbd.X=Z=hydrogen.
[0115] Example 21. A compound of formula I, wherein Q is 32
[0116] W.dbd.X.dbd.Y=hydrogen, and Z=--CH.sub.2CH.dbd.CH.sub.2.
[0117] Example 22. A compound of formula I, wherein Q is 33
[0118] W.dbd.X.dbd.Y=hydrogen, and Z is ethyl.
[0119] Example 23. A compound of formula I, wherein Q is 34
[0120] W.dbd.X.dbd.Y=hydrogen, and Z=--CH.dbd.CHCH.sub.3.
[0121] Example 24. A compound of formula I, wherein Q is 35
[0122] W.dbd.X.dbd.Y=hydrogen, and Z=--CH.sub.2OCH.sub.3.
[0123] Example 25. A compound of formula I, wherein Q is 36
[0124] G=--CH.dbd.CHCH.sub.3 and W=hydrogen.
[0125] Example 26. A compound of formula I, wherein Q is 37
[0126] G=propyl and W=hydrogen.
[0127] Example 27. A compound of formula I, wherein Q is 38
[0128] G=--CH.sub.3 and W=hydrogen.
[0129] The potent immunomodulatory activity which compounds of the
instant invention demonstrate in common in vitro biological assays
(for example, calcineurin phosphatase and binding assays, nuclear
factor of activated T cells (NFAT) reporter gene assay, murine and
human mixed lymphocyte reaction) or animal models (for example
delayed-type hypersensitivity response--DTH,-allergan induced
pulmonary eosinophilia) indicate that these compounds possess
immunosuppressive, antimicrobial, antifungal, antiviral,
antiinflammatory, and antiproliferative activity, and possess the
ability to reverse chemotherapeutic drug resistance. As agents
block T-cell activation, a prerequisite for human immunodeficiency
virus (HIV) proliferation, the compounds are useful as
prophylactics for the prevention of HIV replication. The compounds
of the invention would be useful when used alone, or in combination
therapy with other immunosuppressants, for example, but not limited
to, FK506, rapamycin, cyclosporin A, picibanil, mycophenolic acid,
azathioprine, prednisolone, cyclophosphamide, brequinar and
leflunomide.
[0130] As immunosuppressants, the compounds of the present
invention are useful when administered for the prevention of
immune-mediated tissue or organ graft rejection. Examples of
transplanted tissues and organs which suffer from these effects are
heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas,
intestinum tenue, limb, muscle, nervus, duodenum, small-bowel,
pancreatic-islet-cell, and the like; as well as graft-versus-host
diseases brought about by medulla ossium transplantation. The
regulation of the immune response by the compounds of the invention
would also find utility in the treatment of autoimmune diseases,
such as rheumatoid arthritis, systemic lupus erythematosis,
hyperimmunoglobulin E, Hashimoto's thyroiditis, multiple sclerosis,
progressive systemic sclerosis, myasthenia gravis, type I diabetes,
uveitis, allergic encephalomyelitis, glomerulonephritis, and the
like; and further infectious diseases caused by pathogenic
microorganisms, such as HIV. In the particular cases of HIV-1,
HIV-2 and related retroviral strains, inhibition of T-cell mitosis
would suppress the replication of the virus, since the virus relies
upon the host T-cell's proliferative functions to replicate.
[0131] Further uses include the treatment and prophylaxis of
inflammatory and hyperproliferative skin diseases and cutaneous
manifestations of immunologically-mediated illnesses, such as
psoriasis, atopical dermatitis, contact dermatitis and further
eczematous dermatitises, seborrhoeis dermatitis, Lichen planus,
Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria,
angioedemas, vasculitides, erythemas, cutaneous eosinophilias,
Lupus erythematosus, acne and Alopecia areata; various eye diseases
(autoimmune and otherwise) such as keratoconjunctivitis, vernal
conjunctivitis, keratitis, herpetic keratitis, conical cornea,
dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,
Mooren's ulcer, Scleritis, Graves' opthalmopathy,
Vogt-Koyanagi-Harada syndrome, sarcoidosis, multiple myeloma, etc.;
obstructive airway diseases, which includes conditions such as
chronic obstructive pulmonary disease (COPD), asthma (for example,
bronchial asthma, allergic asthma, intrinsic asthma, extrinsic
asthma and dust asthma), particularly chronic or inveterate asthma
(for example, late asthma and airway hyper-responsiveness),
bronchitis, allergic rhinitis and the like; inflammation of mucosa
and blood vessels such as gastric ulcers, vascular damage caused by
ischemic diseases and thrombosis. Moreover, hyperproliferative
vascular diseases such as intimal smooth muscle cell hyperplasia,
restenosis and vascular occlusion, particularly following
biologically- or mechanically-mediated vascular injury can be
treated or prevented by the compounds of the invention.
[0132] Other treatable conditions would include, but are not
limited to, ischemic bowel diseases, inflammatory bowel diseases,
necrotizing enterocolitis, intestinal lesions associated with
thermal burns and leukotriene B.sub.4-mediated diseases; intestinal
inflammations/allergies such as Coeliac diseases, proctitis,
eosinophilic gastroenteritis, mastocytosis, Crohn's disease and
ulcerative colitis; food-related allergic diseases which have
symptomatic manifestation remote from the gastro-intestinal tract
(e.g., migraine, rhinitis and eczema); renal diseases such as
interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic
syndrome and diabetic nephropathy; nervous diseases such as
multiple myositis, Guillain-Barre syndrome, Meniere's disease,
polyneuritis, multiple neuritis, mononeuritis and radiculopathy;
endocrine diseases such as hyperthyroidism and Basedow's disease;
hematic diseases such as pure red cell aplasia, aplastic anemia,
hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune
hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic
anemia and anerythroplasia; bone diseases such as osteoporosis;
respiratory diseases such as sarcoidosis, fibroid lung and
idiopathic interstitial pneumonia; skin disease such as
dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris,
photoallergic sensitivity and cutaneous T cell lymphoma;
circulatory diseases such as arteriosclerosis, atherosclerosis,
aortitis syndrome, polyarteritis nodosa and myocardosis; collagen
diseases such as scleroderma, Wegener's granuloma and Sjogren's
syndrome; adiposis; eosinophilic fasciitis; periodontal disease
such as lesions of gingiva, periodontium, alveolar bone and
substantia ossea dentis; nephrotic syndrome such as
glomerulonephritis; male pattern aleopecia or alopecia senilis by
preventing epilation or providing hair germination and/or promoting
hair generation and hair growth; muscular dystrophy; Pyoderma and
Sezary's syndrome; Addison's disease; active oxygen-mediated
diseases, as for example organ injury such as ischemia-reperfusion
injury of organs (such as heart, liver, kidney and digestive tract)
which occurs upon preservation, transplantation or ischemic disease
(for example, thrombosis and cardiac infraction): intestinal
diseases such as endotoxin-shock, pseudomembranous colitis and
colitis caused by drug or radiation; renal diseases such as
ischemic acute renal insufficiency and chronic renal insufficiency;
pulmonary diseases such as toxinosis caused by lung-oxygen or drug
(for example, paracort and bleomycins), lung cancer and pulmonary
emphysema; ocular diseases such as cataracta, siderosis, retinitis,
pigmentosa, senile macular degeneration, vitreal scarring and
corneal alkali burn; dermatitis such as erythema multiforme, linear
IgA ballous dermatitis and cement dermatitis; and others such as
gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by
environmental pollution (for example, air pollution), aging,
carcinogenis, metastasis of carcinoma and hypobaropathy; disease
caused by histamine or leukotriene-C.sub.4 release; Behcet's
disease such as intestinal-, vasculo- or neuro-Behcet's disease,
and also Behcet's which affects the oral cavity, skin, eye, vulva,
articulation, epididymis, lung, kidney and so on.
[0133] Furthermore, the compounds of the invention are useful for
the treatment and prevention of hepatic disease such as immunogenic
diseases (for example, chronic autoimmune liver diseases such as
the group consisting of autoimmune hepatitis, primary biliary
cirrhosis and sclerosing cholangitis), partial liver resection,
acute liver necrosis (e.g., necrosis caused by toxin, viral
hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B
hepatitis, cirrhosis (such as alcoholic cirrhosis) and hepatic
failure such as fulminant hepatic failure, late-onset hepatic
failure and "acute-on-chronic" liver failure (acute liver failure
on chronic liver diseases), and moreover are useful for various
diseases because of their useful activity such as augmention of
chemotherapeutic effect, preventing or treating activity of
cytomegalovirus infection, particularly human cytomegalovirus
(HCMV) infection, anti-inflammatory activity, and so on.
[0134] The compounds of the present invention may be used as
vaccines to treat immunosuppression in a subject. It is sometimes
found that the antigen introduced into the body for the acquisition
of immunity from disease also acts as an immunosuppressive agent,
and therefore, antibodies are not produced by the body and immunity
is not acquired. By introducing a compound of the present invention
into the body as a vaccine, the undesired immunosuppression may be
overcome and immunity acquired.
[0135] The compounds of the present invention may also find utility
in the chemosensitization of drug resistant target cells.
Cyclosporin A and FK-506 are known to be effective modulators of
P-glycoprotein, a substance which binds to and inhibits the action
of anticancer drugs by inhibiting P-glycoprotein, as they are
capable of increasing the sensitivity of multidrug resistant (MDR)
cells to chemotherapeutic agents. It is believed that the compounds
of the invention may likewise be effective at overcoming resistance
expressed to clinically useful antitumour drugs such as
5-fluorouracil, cisplatin, methotrexate, vincristine, vinblastine
and adriamycin, colchicine and vincristine.
[0136] Further, it has recently been shown that the steroid
receptor-associated heat shock proteins (hsp), hsp56 or hsp59,
belong to the class of immunophilin proteins (see "HSP70 induction
by cyclosporin A in cultured rat hepatocytes: effect of vitamin E
succinate," Andres, David et al., Instituto de Bioqimica, Facultad
de Farmacia, Universidad Complutense, Madrid, Spain. J. Hepatol.
(2000) 33(4), 570-579; "Cyclosporin A Induces an Atypical Heat
Shock Response," Paslaru, Liliana, et al., Unite de Genetique
Moleculaire, Paris, Fr. Biochem. Biophys. Res. Commun. (2000),
269(2), 464-469; "The cyclosporine A-binding immunophilin CyP-40
and the FK506-binding immunophilin hsp56 bind to a common site on
hsp90 and exist in independent cytosolic heterocomplexes with the
untransformed glucocorticoid receptor," Owens-Grillo, Janet K. et
al., Med. Sch., Univ. Michigan, Ann Arbor, Mich. USA. J. Biol.
Chem. (1995), 270(35), 20479-84). The ability of a steroid
receptor-associated heat shock protein to bind the
immunosuppressive CsA suggests that the steroid receptor and
immunophilin signal transduction pathways are functionally
interrelated. The combined treatment of compounds of the present
invention and low concentrations of a steroid ligand (for e.g.,
progesterone, dexamethasone) result in a significant enhancement of
target gene expression over that seen in response to ligand alone.
Thus, the compounds of the present invention potentiate
steroid-mediated transactivation.
[0137] Aqueous liquid compositions of the present invention may be
particularly useful for the treatment and prevention of various
diseases of the eye such as autoimmune diseases (including, for
example, conical cornea, keratitis, dysophia epithelialis corneae,
leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and
rejection of corneal transplantation.
[0138] Accordingly, the pharmaceutical compositions of the present
invention comprise a therapeutically effective amount of a
cyclosporin analog of the invention (e.g. those of the formulae
delineated herein) in combination with a pharmaceutically
acceptable carrier or excipient. In particular, compositions
pertaining to the present invention are useful for treating a
subject for immune-mediated organ or tissue allograft rejection, a
graft-versus-host disease, an autoimmune disease, an obstructive
airway disease, a hyperproliferative disease, or an ischemic or
inflammatory intestinal or bowel disease.
[0139] The present invention also relates to method(s) of treatment
of immune disorders and inflammation or prevention of organ
transplant rejection in a subject by administering to the subject
therapeutically effective amounts of the cyclosporin analogs of the
present invention with or without the concurrent use of other drugs
or pharmaceutically acceptable excipients, as described throughout
the present specification.
[0140] The methods of the present invention comprise treating a
subject in need of immunosuppresive, anti-inflammatory,
antimicrobial, antifungal, antiviral or antiproliferative therapy,
or requiring the reversal of chemotherapeutic drug resistance, by
administering a therapeutically effective amount of a compound of
the invention for such time and in such amounts as is necessary to
produce the desired result.
[0141] The method includes administering to the subject (including
a subject identified as in need of such treatment) an effective
amount of a compound described herein, or a composition described
herein to produce such effect. Identifying a subject in need of
such treatment can be in the judgment of a subject or a health care
professional and can be subjective (e.g. opinion) or objective
(e.g. measurable by a test or diagnostic method).
[0142] Also within the scope of this invention is a packaged
product. The packaged product includes a container, one of the
aforementioned compounds in the container, and a legend (e.g., a
label or an insert) associated with the container and indicating
administration of the compound for treating a disorder associated
with bacterial infection, including the diseases delineated
herein.
[0143] The present invention also contemplates processes to make
any cyclosporin derivative delineated herein via any synthetic
method delineated herein.
[0144] Definitions
[0145] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification and claims, unless
otherwise limited in specific instances, either individually or as
part of a larger group.
[0146] The terms "C.sub.1-C.sub.3 alkyl," "C.sub.1-C.sub.6 alkyl,"
or "C.sub.1-C.sub.12 alkyl," as used herein, refer to saturated,
straight- or branched-chain hydrocarbon radicals containing between
one and three, one and twelve, or one and six carbon atoms,
respectively. Examples of C.sub.1-C.sub.3 alkyl radicals include
methyl, ethyl, propyl and isopropyl radicals; examples of
C.sub.1-C.sub.6 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl
and n-hexyl radicals; and examples of C.sub.1-C.sub.12 alkyl
radicals include, but are not limited to, ethyl, propyl, isopropyl,
n-hexyl, octyl, decyl, dodecyl radicals.
[0147] The term "substituted alkyl," as used herein, refers to a
"C.sub.2-C.sub.12 alkyl" or "C.sub.1-C.sub.6 alkyl" group as
previously defined, substituted by independent replacement or one,
two, or three of the hydrogen atoms thereon with substituents
including, but not limited to, --F, --Cl, --Br, --I, --OH,
protected hydroxy, --NO.sub.2, --CN, --C.sub.1-C.sub.12-alkyl
optionally substituted with halogen, C.sub.2-C.sub.12-alkenyl
optionally substituted with halogen, --C.sub.2-C.sub.12-alkynyl
optionally substituted with halogen, --NH.sub.2, protected amino,
--NH--C.sub.1-C.sub.12-alkyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.3-C.sub.12-cycloalkyl,
--NH-aryl, --NH-heteroaryl, --NH-heterocycloalkyl, -dialkylamino,
-diarylamino, -diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl, --OCO.sub.2-
C.sub.1-C.sub.12-alkyl, --OCO.sub.2- C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2- C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2-C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12- -alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl, --OCONH--C.sub.3-C.sub.12-cyc-
loalkyl, --OCONH-aryl, --OCONH-heteroaryl,
--OCONH-heterocycloalkyl, --NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl, --NHCO.sub.2-
C.sub.1-C.sub.12-alkyl, --NHCO.sub.2- C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2- C.sub.2-C.sub.12-alkenyl, --NHCO.sub.2-
C.sub.3-C.sub.12-cycloalkyl, --NHCO.sub.2- aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(O)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(O)NH-aryl,
--NHC(O)NH-heteroaryl, --NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl, --NHC(S)NH--C.sub.2-C.s-
ub.12-alkenyl, --NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycl- oalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloa- lkyl,
NHC(NH)-C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH-C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl--SO.sub.2NH.sub.2- ,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alk- enyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.- 12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0148] The terms "C.sub.2-C.sub.12 alkenyl" or "C.sub.2-C.sub.6
alkenyl," as used herein, denote a monovalent group derived from a
hydrocarbon moiety containing from two to twelve or two to six
carbon atoms having at least one carbon-carbon double bond. Alkenyl
groups include, but are not limited to, for example, ethenyl,
propenyl, butenyl, 1-methyl-2-buten-1-yl, 3-hexenyl, and the
like.
[0149] The term "substituted alkenyl," as used herein, refers to a
"C.sub.2-C.sub.12 alkenyl" or "C.sub.2-C.sub.6 alkenyl" group as
previously defined, substituted by independent replacement or one,
two, or three of the hydrogen atoms thereon with substituents
including, but not limited to, --F, --Cl, --Br, --I, --OH,
protected hydroxy, --NO.sub.2, --CN, --C.sub.1-C.sub.12-alkyl
optionally substituted with halogen, C.sub.2-C.sub.12-alkenyl
optionally substituted with halogen, --C.sub.2-C.sub.12-alkynyl
optionally substituted with halogen, --NH.sub.2, protected amino,
--NH--C.sub.1-C.sub.12-alkyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.3-C.sub.12-cycloalkyl,
--NH-aryl, --NH-heteroaryl, --NH-heterocycloalkyl, -dialkylamino,
-diarylamino, -diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2-C.sub.2-C.sub.12-alken- yl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH-C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalky- l, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alke- nyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.1- 2-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0150] The terms "C.sub.2-C.sub.12 alkynyl" or "C.sub.2-C.sub.6
alkynyl," as used herein, denote a monovalent group derived from a
hydrocarbon moiety containing from two to twelve or two to six
carbon atoms having at least one carbon-carbon triple bond by the
removal of a single hydrogen atom. Representative alkynyl groups
include, but are not limited to, for example, ethynyl, 1-propynyl,
1-butynyl, and the like.
[0151] The term "substituted alkynyl," as used herein, refers to a
"C.sub.2-C.sub.12 alkynyl" or "C.sub.2-C.sub.6 alkynyl" group as
previously defined, substituted by independent replacement or one,
two, or three of the hydrogen atoms thereon with substituents
including, but not limited to, --F, --Cl, --Br, --I, --OH,
protected hydroxy, --NO.sub.2, --CN, --C.sub.1-C.sub.12-alkyl
optionally substituted with halogen, C.sub.2-C.sub.12-alkenyl
optionally substituted with halogen, --C.sub.2-C.sub.12-alkynyl
optionally substituted with halogen, --NH.sub.2, protected amino,
--NH--C.sub.1-C.sub.12-alkyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.3-C.sub.12-cycloalkyl,
--NH-aryl, --NH-heteroaryl, --NH-heterocycloalkyl, -dialkylamino,
-diarylamino, -diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2- heteroaryl, --NHCO.sub.2- heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkeny- l,
--NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)NH-aryl,
--NHC(O)NH-heteroaryl, --NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alke- nyl,
--SO.sub.2NH-C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.12- -cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2--C.sub.2-C.sub.12-al- kenyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0152] The term "C.sub.1-C.sub.6 alkoxy," as used herein, refers to
a C.sub.1-C.sub.6 alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom. Examples of
C.sub.1-C.sub.6-alkoxy include, but are not limited to, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and
n-hexoxy.
[0153] The terms "halo" and "halogen," as used herein, refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0154] The term "aryl," as used herein, refers to a mono- or
bicyclic carbocyclic ring system having one or two aromatic rings
including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, idenyl and the like.
[0155] The term "substituted aryl," as used herein, refers to an
aryl group, as previously defined, substituted by independent
replacement or one, two, or three of the hydrogen atoms thereon
with substituents including, but not limited to, --F, --Cl, --Br,
--I, --OH, protected hydroxy, --NO.sub.2, --CN,
--C.sub.1-C.sub.12-alkyl optionally substituted with halogen,
C.sub.2-C.sub.12-alkenyl optionally substituted with halogen,
--C.sub.2-C.sub.12-alkynyl optionally substituted with halogen,
--NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)-C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH-C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH-C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalky- l, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alke- nyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.1- 2-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0156] The term "arylalkyl," as used herein, refers to a
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.6 alkyl residue attached to
an aryl ring. Examples include, but are not limited to, benzyl,
phenethyl and the like.
[0157] The term "substituted arylalkyl," as used herein, refers to
an arylalkyl group, as previously defined, substituted by
independent replacement or one, two, or three of the hydrogen atoms
thereon with substituents including, but not limited to, but not
limited to, --F, --Cl, --Br, --I, --OH, protected hydroxy,
--NO.sub.2, --CN, --C.sub.1-C.sub.12-alkyl optionally substituted
with halogen, C.sub.2-C.sub.12-alkenyl optionally substituted with
halogen, --C.sub.2-C.sub.12-alkynyl optionally substituted with
halogen, --NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O-C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)-C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH-C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl--SO.sub.2NH.sub.2- ,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alk- enyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.- 12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0158] The term "heteroaryl," as used herein, refers to a mono-,
bi-, or tri-cyclic aromatic radical or ring having from five to ten
ring atoms of which one ring atom is selected from S, O and N;
zero, one or two ring atoms are additional heteroatoms
independently selected from S, O and N; and the remaining ring
atoms are carbon, wherein any N or S contained within the ring may
be optionally oxidized. Heteroaryl includes, but is not limited to,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,
benzooxazolyl, quinoxalinyl, and the like.
[0159] The term "substituted heteroaryl," as used herein, refers to
a heteroaryl group as previously defined, substituted by
independent replacement or one, two, or three of the hydrogen atoms
thereon with substituents including, but not limited to, --F, --Cl,
--Br, --I, --OH, protected hydroxy, --NO.sub.2, --CN,
--C.sub.1-C.sub.12-alkyl optionally substituted with halogen,
C.sub.2-C.sub.12-alkenyl optionally substituted with halogen,
--C.sub.2-C.sub.12-alkynyl optionally substituted with halogen,
--NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alke- nyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.1- 2-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0160] The term "C.sub.3-C.sub.12-Cycloalkyl," as used herein,
denotes a monovalent group derived from a monocyclic or bicyclic
saturated carbocyclic ring compound by the removal of a single
hydrogen atom. Examples include, but not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and
bicyclo [2.2.2] octyl.
[0161] The term "substituted C.sub.3-C.sub.12-cycloalkyl," as used
herein, refers to a C.sub.3-C.sub.12-cycloalkyl group as previously
defined, substituted by independent replacement or one, two, or
three of the hydrogen atoms thereon with substituents including,
but not limited to, --F, --Cl, --Br, --I, --OH, protected hydroxy,
--NO.sub.2, --CN, --C.sub.1-C.sub.12-alkyl optionally substituted
with halogen, C.sub.2-C.sub.12-alkenyl optionally substituted with
halogen, --C.sub.2-C.sub.12-alkynyl optionally substituted with
halogen, --NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)- heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH-C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl--SO.sub.2NH.sub.2- ,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alk- enyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.- 12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0162] The term "heterocycloalkyl," as used herein, refers to a
non-aromatic 5-, 6- or 7-membered hydrocarbon ring or a bi- or
tri-cyclic group fused hydrocarbon system, where (i) each ring
contains between one and three heteroatoms independently selected
from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0
to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,
(iii) the nitrogen and sulfur heteroatoms may optionally be
oxidized, (iv) the nitrogen heteroatom may optionally be
quaternized, and (iv) any of the above rings may be fused to a
benzene ring. Representative heterocycloalkyl groups include, but
are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
[0163] The term "substituted heterocycloalkyl," as used herein,
refers to a heterocycloalkyl group, as previously defined,
substituted by independent replacement or one, two, or three of the
hydrogen atoms thereon with substituents including, but not limited
to, --F, --Cl, --Br, --I, --OH, protected hydroxy, --NO.sub.2,
--CN, --C.sub.1-C.sub.12-alkyl optionally substituted with halogen,
C.sub.2-C.sub.12-alkenyl optionally substituted with halogen,
--C.sub.2-C.sub.12-alkynyl optionally substituted with halogen,
--NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O-C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alke- nyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.1- 2-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2-C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0164] The term "heteroarylalkyl," as used herein, refers to a
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.6 alkyl residue residue
attached to a heteroaryl ring. Examples include, but are not
limited to, pyridinylmethyl, pyrimidinylethyl and the like.
[0165] The term "substituted heteroarylalkyl," as used herein,
refers to a heteroarylalkyl group, as previously defined,
substituted by independent replacement or one, two, or three of the
hydrogen atoms thereon with substituents including, but not limited
to, --F, --Cl, --Br, --I, --OH, protected hydroxy, --NO.sub.2,
--CN, --C.sub.1-C.sub.12-alkyl optionally substituted with halogen,
C.sub.2-C.sub.12-alkenyl optionally substituted with halogen,
--C.sub.2-C.sub.12-alkynyl optionally substituted with halogen,
--NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-- alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2-C.sub.2-C.sub.12-alken- yl,
--OCO.sub.2-C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl- , --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl, --NHCO.sub.2-
C.sub.1-C.sub.12-alkyl, --NHCO.sub.2--C.sub.2-C.sub.12-alke- nyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.1- 2-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, NHC(O)NH--C.sub.1-C.sub.- 12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl, --NHC(O)NH--C.sub.2-C.sub.-
12-alkenyl, --NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl,
--NHC(O)NH-aryl, --NHC(O)NH-heteroaryl,
--NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloa- lkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alke- nyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalk- yl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalk- yl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alke- nyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.1- 2-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2-C.sub.2-C.sub.12-alk- enyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycl- oalkyl, -methoxymethoxy, -methoxyethoxy,
--SH, --S--C.sub.1-C.sub.12-alkyl- , --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.3-C.sub.12-cycloalkyl,
--S-aryl, --S-heteroaryl, --S-heterocycloalkyl, or
methylthiomethyl.
[0166] The term "C.sub.1-C.sub.3-alkyl-amino," as used herein,
refers to one or two C.sub.1-C.sub.3-alkyl groups, as previously
defined, attached to the parent molecular moiety through a nitrogen
atom. Examples of C.sub.1-C.sub.3-alkyl-amino include, but are not
limited to, methylamino, dimethylamino, ethylamino, diethylamino,
and propylamino.
[0167] The term "alkylamino" refers to a group having the structure
--NH(C.sub.1-C.sub.12 alkyl) where C.sub.1-C.sub.12 alkyl is as
previously defined.
[0168] The term "dialkylamino" refers to a group having the
structure --N(C.sub.1-C.sub.12 alkyl) (C.sub.1-C.sub.12 alkyl),
where C.sub.1-C.sub.12 alkyl is as previously defined. Examples of
dialkylamino are, but not limited to, dimethylamino, diethylamino,
methylethylamino, piperidino, and the like.
[0169] The term "alkoxycarbonyl" represents an ester group, i.e.,
an alkoxy group, attached to the parent molecular moiety through a
carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the
like.
[0170] The term "carboxaldehyde," as used herein, refers to a group
of formula --CHO.
[0171] The term "carboxy," as used herein, refers to a group of
formula --COOH.
[0172] The term "carboxamide," as used herein, refers to a group of
formula --C(O)NH(C.sub.1-C.sub.12 alkyl) or
--C(O)N(C.sub.1-C.sub.12 alkyl) (C.sub.1-C.sub.12 alkyl),
--C(O)NH.sub.2, and the like.
[0173] The term "hydroxy protecting group," as used herein, refers
to a labile chemical moiety which is known in the art to protect a
hydroxyl group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the hydroxy
protecting group as described herein may be selectively removed.
Hydroxy protecting groups as known in the are described generally
in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
Examples of hydroxy protecting groups include, but are not limited
to, methylthiomethyl, tert-butyl-dimethylsilyl,
tert-butyldiphenylsilyl, acyl substituted with an aromatic group
and the like.
[0174] The term "protected hydroxy," as used herein, refers to a
hydroxy group protected with a hydroxy protecting group, as defined
above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl groups, for example.
[0175] The term "amino protecting group," as used herein, refers to
a labile chemical moiety which is known in the art to protect an
amino group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the amino protecting
group as described herein may be selectively removed. Amino
protecting groups as known in the are described generally in T. H.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd edition, John Wiley & Sons, New York (1999). Examples of
amino protecting groups include, but are not limited to,
t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl,
and the like.
[0176] The term "protected amino," as used herein, refers to an
amino group protected with an amino protecting group as defined
above.
[0177] The term "aprotic solvent," as used herein, refers to a
solvent that is relatively inert to proton activity, i.e., not
acting as a proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
compounds are well known to those skilled in the art, and it will
be obvious to those skilled in the art that individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of aprotic solvents may be
found in organic chemistry textbooks or in specialized monographs,
for example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick et aL, Vol. II, in
the Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
[0178] The term "protogenic organic solvent," as used herein,
refers to a solvent that tends to provide protons, such as an
alcohol, for example, methanol, ethanol, propanol, isopropanol,
butanol, t-butanol, and the like. Such solvents are well known to
those skilled in the art, and it will be obvious to those skilled
in the art that individual solvents or mixtures thereof may be
preferred for specific compounds and reaction conditions, depending
upon such factors as the solubility of reagents, reactivity of
reagents and preferred temperature ranges, for example. Further
discussions of protogenic solvents may be found in organic
chemistry textbooks or in specialized monographs, for example:
Organic Solvents Physical Properties and Methods of Purification,
4th ed., edited by John A. Riddick et al., Vol. II, in the
Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
[0179] "An effective amount," as used herein, refers to an amount
of a compound which confers a therapeutic effect on the treated
subject. The therapeutic effect may be objective (i.e., measurable
by some test or marker) or subjective (i.e., subject gives an
indication of or feels an effect). An effective amount of the
compound described above may range from about 0.1 mg/Kg to about
500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective
doses will also vary depending on route of administration, as well
as the possibility of co-usage with other agents.
[0180] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds. The term "stable", as used herein, refers to
compounds which possess stability sufficient to allow manufacture
and which maintains the integrity of the compound for a sufficient
period of time to be useful for the purposes detailed herein (e.g.,
therapeutic or prophylactic administration to a subject).
[0181] The synthesized compounds can be separated from a reaction
mixture and further purified by a method such as column
chromatography, high pressure liquid chromatography, or
recrystallization. As can be appreciated by the skilled artisan,
further methods of synthesizing the compounds of the formulae
herein will be evident to those of ordinary skill in the art.
Additionally, the various synthetic steps may be performed in an
alternate sequence or order to give the desired compounds.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the compounds described herein are known in the art and include,
for example, those such as described in R. Larock, Comprehensive
Organic Transformations, VCH Publishers (1989); T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John
Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995), and subsequent editions thereof.
[0182] The term "subject" as used herein refers to an animal.
Preferably the animal is a mammal. More preferably the mammal is a
human. A subject also refers to, for example, dogs, cats, horses,
cows, pigs, guinea pigs, fish, birds and the like.
[0183] The compounds of this invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. Such modifications are known in the art and may include
those which increase biological penetration into a given biological
system (e.g., blood, lymphatic system, central nervous system),
increase oral availability, increase solubility to allow
administration by injection, alter metabolism and alter rate of
excretion.
[0184] The compounds described herein contain one or more
asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)-- or (S)--, or as (D)-
or (L)- for amino acids. The present invention is meant to include
all such possible isomers, as well as their racemic and optically
pure forms. Optical isomers may be prepared from their respective
optically active precursors by the procedures described above, or
by resolving the racemic mixtures. The resolution can be carried
out in the presence of a resolving agent, by chromatography or by
repeated crystallization or by some combination of these techniques
which are known to those skilled in the art. Further details
regarding resolutions can be found in Jacques, et al., Enantiomers,
Racemates, and Resolutions (John Wiley & Sons, 1981). When the
compounds described herein contain olefinic double bonds, other
unsaturation, or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers or cis- and trans-isomers. Likewise, all
tautomeric forms are also intended to be included. The
configuration of any carbon-carbon double bond appearing herein is
selected for convenience only and is not intended to designate a
particular configuration unless the text so states; thus a
carbon-carbon double bond or carbon-heteroatom double bond depicted
arbitrarily herein as trans may be cis, trans, or a mixture of the
two in any proportion.
[0185] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et aL. describes
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 1-19 (1977). The salts can be prepared in situ during
the final isolation and purification of the compounds of the
invention, or separately by reacting the free base function with a
suitable organic acid. Examples of pharmaceutically acceptable
include, but are not limited to, nontoxic acid addition salts are
salts of an amino group formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid
and perchloric acid or with organic acids such as acetic acid,
maleic acid, tartaric acid, citric acid, succinic acid or malonic
acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include, but are
not limited to, adipate, alginate, ascorbate, aspartate,
benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,
sulfonate and aryl sulfonate.
[0186] As used herein, the compounds of this invention, including
the compounds of formulae described herein, are defined to include
pharmaceutically acceptable derivatives or prodrugs thereof. A
"pharmaceutically acceptable derivative or prodrug" means any
pharmaceutically acceptable salt, ester, salt of an ester, or other
derivative of a compound of this invention which, upon
administration to a recipient, is capable of providing (directly or
indirectly) a compound of this invention.
[0187] When the compositions of this invention comprise a
combination of a compound of the formulae described herein and one
or more additional therapeutic or prophylactic agents, both the
compound and the additional agent should be present at dosage
levels of between about 1 to 100%, and more preferably between
about 5 to 95% of the dosage normally administered in a monotherapy
regimen. The additional agents may be administered separately, as
part of a multiple dose regimen, from the compounds of this
invention. Alternatively, those agents may be part of a single
dosage form, mixed together with the compounds of this invention in
a single composition.
[0188] Pharmaceutical Compositions
[0189] The pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound or
compounds of the present invention (e.g. those of the formulae
delineated herein) formulated together with one or more
pharmaceutically acceptable carriers or excipients.
[0190] As used herein, the term "pharmaceutically acceptable
carrier or excipient" means a non-toxic, inert solid, semi-solid or
liquid filler, diluent, encapsulating material or formulation
auxiliary of any type. Some examples of materials which can serve
as pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
glycols such as propylene glycol; esters such as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide
and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions, as well as other non-toxic compatible lubricants such as
sodium lauryl sulfate and magnesium stearate, as well as coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0191] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir, preferably by oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids,
bases or buffers to enhance the stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0192] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0193] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0194] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0195] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions that are compatible with body tissues.
[0196] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0197] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0198] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0199] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes.
[0200] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0201] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0202] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0203] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0204] According to the methods of treatment of the present
invention, immune disorders are treated or prevented in a patient
such as a human or other animals by administering to the patient a
therapeutically effective amount of a compound of the invention, in
such amounts and for such time as is necessary to achieve the
desired result.
[0205] By a "therapeutically effective amount" of a compound of the
invention is meant a sufficient amount of the compound to treat the
immune disorders delineated herein, at a reasonable benefit/risk
ratio applicable to any medical treatment. It will be understood,
however, that the total daily usage of the compounds and
compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or contemporaneously with the specific compound employed; and like
factors well known in the medical arts.
[0206] The compounds of the formulae described herein can, for
example, be administered by injection, intravenously,
intraarterially, subdermally, intraperitoneally, intramuscularly,
or subcutaneously; or orally, buccally, nasally, transmucosally,
topically, in an ophthalmic preparation, or by inhalation, with a
dosage ranging from about 0.5 to about 100 mg/kg of body weight,
alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120
hours, or according to the requirements of the particular drug. The
methods herein contemplate administration of an effective amount of
compound or compound composition to achieve the desired or stated
effect. Typically, the pharmaceutical compositions of this
invention will be administered from about 1 to about 6 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy. The amount of active
ingredient that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the host
treated and the particular mode of administration. A typical
preparation will contain from about 5% to about 95% active compound
(w/w). Alternatively, such preparations may contain from about 20%
to about 80% active compound.
[0207] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
patient will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the patient's disposition to the
disease, condition or symptoms, and the judgment of the treating
physician.
[0208] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level. Patients may, however, require intermittent treatment on a
long-term basis upon any recurrence of disease symptoms.
[0209] Immunosuppression Activity
Calcineurin Inhibition Assay
[0210] The immunosuppressive activity of cyclosporin is mediated
through inhibition of the phosphatase activity of the enzyme
calcineurin by a cyclophilin-cyclosporin complex. Thus, calcineurin
inhibition is widely used as an in vitro measure of the activity of
cyclosporin analogs.
[0211] Compounds were tested in an assay based on the Biomol Green
Calcineurin Assay Kit supplied by Biomol (Plymouth Meeting, Pa.),
supplemented with cyclophilin A for enzyme inhibition. The activity
of the recombinant human calcineurin was determined by release of
phosphate from a phosphopeptide representing a fragment of
camp-dependent protein kinase. Phosphate release was determined
using the colorimetric detection reagent Biomol Green.
[0212] Compounds in dimethyl sulfoxide (DMSO) (2.4 .mu.l) were
added to a 96-well microplate and mixed with 50 .mu.l assay buffer
(50 mM Tris, pH 7.5, 0.1 M sodium chloride, 6 mM magnesium
chloride, 0.5 mM dithiothreitol, 0.025% NP-40, 0.5 mM calcium
chloride, 0.25 .mu.M calmodulin) containing 5 .mu.M cyclophilin and
20 units of calcineurin. After warming to 37.degree. C. for 15 min,
the enzymatic reaction was initiated by addition of phosphopeptide
(7.5 .mu.l) to give a final concentration of 94 .mu.M. Phosphate
release after 60 min at 37.degree. C. was determined by addition of
Biomol Green (100 .mu.l) and measurement of the absorbance at 620
nm after 15 min at room temperature.
[0213] IC.sub.50 values were calculated from determinations of
enzyme activity at inhibitor concentrations ranging from 20 to
0.006 .mu.M.
Murine Mixed Lymphocyte Reaction
[0214] Approximately 0.5.times.10.sup.6 lymphocytes from the spleen
of female (8-10 weeks) Balb/c mice are incubated for 5 days in 0.2
ml cell growth medium with ca. 0.5.times.10.sup.6 lymphocytes from
the spleen of female (8-10 weeks) albino brown agouti (CBA) mice.
Test substance is added to the medium at various concentrations.
Activity is assessed by ability to suppress
proliferation-associated DNA synthesis as determined by
incorporation of radiolabelled thymidine.
Mishell-Dutton Test
[0215] Approximately 10.sup.7 lymphocytes from the spleen of CF1,
female mice are co-cultured with ca. 3.times.10.sup.7 sheep
erythrocytes for 3 days. Test substance is added to the incubation
medium in varying concentrations. Lymphocytes are harvested and
plated onto agar with fresh sheep erythrocytes as antigen.
Sensitized lymphocytes secrete antibody that coats the
erythrocytes, which lyse to form a plaque in the presence of
complement. Activity is assessed by reduction in the number of
plaque forming, i.e., antibody product, cells.
Influence on Allergen-induced Pulmonary Eosinophilia (in vitro)
[0216] Male Himalayan spotted guinea pigs (300 g, BRL) are
sensitized to ovalbumin (OA) by i.p. injection of 1 ml of a
suspension of OA (10 .mu.g/ml) with Al(OH).sub.3 (100 mg) and
B-pertussis vaccine (0.25 ml) in saline (0.9% w/v). For oral
studies the procedure is repeated 1.times. after 2 weeks and the
animals are used one week later. For inhalation studies the
procedure is repeated 2.times. at 3-week intervals and the animals
are used one week after the last injection.
[0217] Challenge is affected employing a saline solution of OA,
nebulized for discharge into an exposure chamber. Test animals are
exposed to OA by nose-only inhalation for 60 minutes. For
inhalation studies, OA solution is used at a concentration of
0.01%.
[0218] Test substance is administered by inhalation and/or orally.
For oral studies, test substance is administered p.o. in olive oil
1.times. daily for 3 days or in powder form in methylcellulose once
prior to OA challenge. On day 3, test animals receive test
substance 1.5 hours prior to and 6 hours after OA challenge. For
inhalation studies, test substance is micronised for delivery to
test animals restrained within a flow-past, nose-only inhalation
chamber. Administration by inhalation is effected 15 minutes prior
to OA challenge.
[0219] Efficacy of administered test substance is determined by
bronchoalveolar lavage (BAL) and cell counting. For this purpose
animals are sacrificed with Na pento-barbitone (100 mg/kg i.p.) and
the trachea is exposed and cannulated. 5 successive 10 ml aliqots
of Ca.sup.2+ and Mg.sup.2+ free Hank's balanced salt solution
(HBSS), containing bovine serum albumin (BSA, 0.3%), EDTA (10 mM)
and 4-(2-hydroxyethyl)-1-piperazi- neethanesulfonic acid (HEPES)
(10 mM) is then introduced into the lung and immediately aspirated
by gentle compression of the lung tissue. Total cell counts in
pooled eluates are determined using an automatic cell counter.
Lavage fluid is centrifuged at 200g for 10 minutes and the cell
pellet resuspended in 1 ml of supplemented HBSS. 10 .mu.l of this
cell suspension is added to 190 .mu.l of Turk's solution (1:20)
dilution). Differential cell counts are made from smears stained by
Diff-Quick. Cells are identified and counted under oil immersion
(.times.1,000). A minimum of 500 cells per smear are counted and
the total population of each cell type is calculated.
[0220] Unless otherwise defined, all technical and scientific terms
used herein are accorded the meaning commonly known to one with
ordinary skill in the art. All publications, patents, published
patent applications, and other references mentioned herein are
hereby incorporated by reference in their entirety.
[0221] Abbreviations
[0222] Abbreviations which may be used in the descriptions of the
scheme and the examples that follow are:
[0223] Ac for acetyl;
[0224] AIBN for azobisisobutyronitrile;
[0225] Bu.sub.3SnH for tributyltin hydride;
[0226] CDI for carbonyldiimidazole;
[0227] dba for dibenzylidene acetone;
[0228] dppb for diphenylphosphino butane;
[0229] DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;
[0230] DEAD for diethylazodicarboxylate;
[0231] DIBAL-H for diisopropyl aluminum hydride;
[0232] DMAP for dimethylaminopyridine;
[0233] DMF for dimethyl formamide;
[0234] DPPA for diphenylphosphoryl azide;
[0235] LAH for lithium aluminum hydride;
[0236] EtOAc for ethyl acetate;
[0237] MeOH for methanol;
[0238] NaN(TMS).sub.2 for sodium bis(trimethylsilyl)amide;
[0239] NMMO for N-methylmorpholine N-oxide;
[0240] TEA for triethylamine;
[0241] THF for tetrahydrofuran;
[0242] TPP or PPh.sub.3 for triphenylphosphine;
[0243] MOM for methoxymethyl;
[0244] Boc for t-butoxycarbonyl;
[0245] Bz for benzyl;
[0246] Ph for phenyl;
[0247] POPd for dihydrogen
dichlorobis(di-tert-butylphosphinito-.kappa.P)p- alladate(II);
[0248] Py for pyridine;
[0249] TBS for tert-butyl dimethylsilyl;
[0250] TMS for trimethylsilyl;
[0251] TES for trimethylsilyl;
[0252] Sar for Sarcosine;
[0253] MeLeu for N-Methyl-Leucine;
[0254] Val for valine;
[0255] Ala for Alanine;
[0256] MeVal for N-Methyl Valine;
[0257] Et for Ethyl;
[0258] Ph for Phenyl; and
[0259] MeBmt for N-Methyl-butenyl-threonine.
[0260] Synthetic Methods
[0261] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes that illustrate the methods by which the compounds of the
invention may be prepared.
[0262] The synthetic schemes contained herein refer to
modifications to formula A of formula 1, as previously defined.
39
[0263] Cyclosporin A (CsA) can be converted to aldehyde (1-2)
through first protecting the hydroxy of the MeBmt residue of CsA as
an acetate ester to form a compound of formula (1-1). Other
suitable hydroxy protecting groups include, but are not limited to,
TMS, TES, TBS, or COCF.sub.3 (for further details concerning these
and other hydroxy protecting groups known in the art, as well as
there incorporation and removal, please see T. W. Greene and P. G.
M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John
Wiley and Sons (1991).) Aldehyde (1-2) can then be formed through
creation of the corresponding diol by treatment with OSO.sub.4
followed by the oxidative cleavage of the resulting diol with
NaIO.sub.4 (for further details of diol formation with OSO.sub.4,
please see Akashi, K, Palermo, R. E., Sharpless, K. B., J. Org.
Chem. 1978, 43, 2003-06; and for further details concerning the
oxidative cleavage of diols with NaIO.sub.4, please see Zhong, Y.
L., Shing, T. K. M., J. Org. Chem. 1997, 62, 2622-24). This
reaction may also be performed through ozonolysis (see Park, S. B.,
Meier, G. P. Tetrahedron Lett. 1989, 30, 4215-4218). 40
[0264] Compound of formula (1-2) may be treated with vinyl Grignard
reagent of formula (2-1), where X, Y, and Z are as previously
defined, to form the allyl alcohol (2-2), where W, X, Y, and Z are
as previously defined. The requisite Grignard reagents are readily
available via the reaction of a variety of vinyl halides with
magnesium under standard conditions (for further details, please
see B. S. Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell
"Vogel's Textbook of Practical Organic Chemistry" 5th ed., Longman,
1989 or G. S. Silverman, P. E. Rakita in Kirk-Othmer Encyclopedia
of Chemical Technology vol. 12 (Wiley-Interscience, New York, 4th
ed., 1994) pp 768-786). The addition is performed in an inert
solvent, generally at low temperature. Suitable solvents include,
but are not limited to tetrahydrofuran, diethylether, 1,4-dioxane,
1,2-dimethoxyethane, and hexanes. Preferably the solvent is
tetrahydrofuran or diethylether. Preferably the reaction is run at
-78.degree. to 0.degree. C.
[0265] Allyl alcohol of formula (2-2) is then protected with a
hydroxy protecting group to form a compound of formula (2-3).
Suitable hydroxy protecting groups include, but are not limited to,
acetate and methyl carbamate (for further details on suitable
hydroxy protecting groups see T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and
Sons (1991)). The protected allylic alcohol then undergoes a
palladium-catalyzed elimination to form conjugated diene compound
of formula (2-4) (for further details, please see Tsuji, J. et al,
Tetrahedron Lett. 1978, 24, 2075-2078). Suitable solvents include,
but are not limited to, dioxane, toluene, or t-butyl alcohol. A
suitable palladium catalyst is palladium acetate in the presence of
triphenylphosphine or (PPh.sub.3).sub.4Pd. Suitable reaction
conditions are at a temperature up to reflux for a duration of at
least one hour. 41
[0266] Compounds of the invention according to formula (2-4) are
also capable of further functionalization to generate compounds of
the present invention. Alkene (2-4) can be treated with an aryl
halide or aryl triflate in the presence of a palladium catalyst
[Pd(0) or Pd(II)] to provide compound (3-1): (See (a) Heck,
Palladium Reagents in Organic Synthesis, Academic Press: New York,
1985, Chapter 1; (b) Sonogashira, Comprehensive Organic Synthesis,
Volume 3, Chapters 2,4; (c) Sonogashira, Synthesis 1977, 777.).
Under the Heck coupling conditions, regioisomers and stereoisomers
of the double bond are possible. Alternatively, compound (2-4) can
undergo a cross metathesis reaction with vinyl derivatives using
ruthenium catalysts to give compounds of formula (3-2), where
R.sub.1 is as previously defined (see (a) J. Org. Chem. 2000, 65,
2204-2207; (b) Reviews: Synlett. 1999, 2, 267; (c) Reviews: Ivin,
K. J.; Mol, J. C. Olefin Metathesis and Metathesis Polymerization,
2.sup.nd ed.; Academic Press: New York, 1997; (d) J. Org. Chem.
1999, 64, 4798-4816; (e) Angew. Chem., Int. Ed. Engl. 1997, 36,
2036-2056; (f) Tetrahedron 1998, 54, 4413-4450; (e) Connon, S. J.
and Blechert, S. Angew. Chem. Int. Ed. 2003, 42,1900-23). In
addition, compound of formula (2-4) may be subjected to cross
metathesis reaction conditions in the presence of compounds of
formula (3-3), where R.sub.1 is as previously defined, to yield
conjugated esters of formula (3-4). 42
[0267] Compound of formula (1-2) may be treated with lithium
acetylide of formula (4-1), where G is as previously defined, to
form the propargyl alcohol (4-2). The requisite lithium reagents
are readily available via the reaction of a variety of acetylenes
with n-butyl lithium under standard conditions (for further
details, please see B. S. Furniss, A. J. Hannaford, P. W. G. Smith,
A. R. Tatchell "Vogel's Textbook of Practical Organic Chemistry"
5.sup.th ed., Longman, 1989 or G. S. Silverman, P. E. Rakita in
Kirk-Othmer Encyclopedia of Chemical Technology vol. 12
(Wiley-lnterscience, New York, 4th ed., 1994)). The reaction can be
performed in an inert solvent, generally at low temperature.
Suitable solvents include, but are not limited to tetrahydrofuran,
diethylether, 1,4-dioxane, 1,2-dimethoxyethane, and hexanes.
Preferably the solvent is tetrahydrofuran or diethylether.
Preferably the reaction is run at -78.degree..
[0268] Propargyl alcohol of formula (4-2) is then activated with a
an electron-withdrawing group (EWG) to form a compound of formula
(4-3). Suitable hydroxy activating groups include, but are not
limited to, mesylate and triflate. The activated propargyl alcohol
then undergoes elimination to form conjugated ene-yne compound of
formula (4-4) (for further details, please see Tsuji, J. et al,
Tetrahedron Lett. 1978, 24, 2075-2078). Suitable solvents include,
but are not limited to, toluene or THF. Suitable reaction
conditions are at a temperature up to reflux. 43
[0269] Compound of formula (4-4), where G is as previously defined,
can undergo catalytic hydrogenation via Lindlar's catalyst to yield
the cis conjugated diene of formula (5-1) (for further details,
please see H. Lindlar and R. Dubois, Org Synth. V, 880 (1973)). In
addition, compound of formula (4-4), when G=H, may be treated with
aryl halides under Sonagashira conditions to afford compounds of
formula (5-2) (for further details of the Sonogashira reaction see
Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2,
4 and Sonogashira, Synthesis 1977, 777).
EXAMPLES
[0270] The procedures described above for preparing the compounds
of the present invention will be better understood in connection
with the following examples, which are intended to be illustrative
only and not limiting of the scope of the invention. Various
changes and modifications of the disclosed embodiments will be
apparent to those skilled in the art. Such changes and
modifications, including without limitation, those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods for the invention may be
made without departing from the spirit of the invention and the
scope of the appended claims.
Example 1
[0271] A compound of formula I, wherin A is of the formula (1-2)
and W is Ac.
[0272] Step a. A compound of formula 1, wherein A is of the formula
(1-1) and W is Ac.
[0273] To a solution of cyclosporine A (105 g, 87.42 mmol), DMAP
(1.0 g, 8.18 mmol, 9.4% eq), Py (16 ml, 197.8 mmol, 2.26 eq ) in
CH.sub.2Cl.sub.2 (100 ml) at 0.degree. C. is added Ac.sub.2O (30
ml, 317.65 mmol, 3.63 eq). The mixture is stirred from 0.degree. C.
to room temperature over night. After the reaction is complete as
judged by mass spectrometry analysis, solvent (CH.sub.2Cl.sub.2) is
removed under vacuum. The white solid residue is dissolved in ethyl
acetate, washed with water (300 ml), 1.0 HCl (2.times.200 ml),
water (200 ml), sat. NaHCO.sub.3 (200 ml), brine (200 ml), dried
with Na.sub.2SO.sub.4, filtered and evaporated. The residue is
lyophilized to give a white solid. m/e.sup.+ for
C.sub.64H.sub.113N.sub.11O.sub.13 1243.85, found 1244.51
(m+H).sup.+, 1266.52 (m+Na).sup.+
[0274] Step b. A compound of formula I, wherein A is of the formula
(1-2) and W is Ac.
[0275] To a solution of cyclosporine A acetate from Step a (40.2 g,
32.32 mmol) in acetone (300 ml)-H.sub.2O (100 ml) at room
temperature is added OSO.sub.4 (58 mg, 0.228 mmol, 0.7% eq). The
solution becomes black immediately. Then NaIO.sub.4 (34.7 g, 162.23
mmol, 5.0 eq) is added. The black color fads and white solid
precipitates out upon stirring. The reaction is monitored by TLC
and mass spectrometry analysis. Upon the completion of the
reaction, the mixture is concentrated under vacuum in a hood to
remove most of the acetone. The residue is extracted with ethyl
acetate. The organic solution is washed with water (1.times.200
ml), aqueous sodium sulfite solution until the aqueous layer is
colorless (yellow color indicated the presence of oxidizing agent
such NaIO.sub.4), sat. NaHCO.sub.3 (to remove acid by-product),
water again and finally washed with brine. After drying with
Na.sub.2SO.sub.4, the solution is evaporated and lyophilized to
give the title compound as a white solid. The crude product might
be purified by silica gel chromatography (eluted with 50% ethyl
acetate-hexane, then 100% ethyl acetate). m/e.sup.+for
C.sub.62H.sub.109N.sub.11O.sub.14 1231.82, found 1232.22
(m+H).sup.+, 1249.26, (m+NH.sub.4).sup.+, 1254.19 (m+Na).sup.+.
Example 2
[0276] A compound of formula I, wherein Q is 44
[0277] W is Ac and X.dbd.Y=Z=hydrogen.
[0278] Step a. A compound of formula I: A is formula (2-2), wherein
X.dbd.Y=Z=hydrogen.
[0279] A solution of vinylmagnesium bromide (40 ml, 0.5 M in THF,
20 mmol) is diluted with 50 ml THF and cooled to -78.degree. C.
Then a solution of the title compound from Example 1 (4.3 g, 3.49
mmol) in THF (2 ml) is added dropwise. After addition, the mixture
is stirred for 20-30 min and quenched with aq. NH.sub.4Cl at
-78.degree. C. After warm up to room temperature, the mixture is
extracted with ethyl acetate (2.times.100 ml). The combined organic
solution is washed with brine, dried with Na.sub.2SO.sub.4,
concentrated and dried by lyophilization to afford a light yellow
solid (4.66 g). m/e.sup.+ for C.sub.64H.sub.113N.sub.11O.sub- .14
1259.85, found 1282.90 (m+Na).sup.+.
[0280] Step b. A compound of formula I: A is formula (2-3), wherein
X.dbd.Y=Z=hydrogen
[0281] To a solution of cyclosporine A allyl alcohol of Step a
(4.66 g, 3.77 mmol), DMAP (45 mg, 0.36 mmol, 9.5% eq), Py (0.72 ml,
8.90 mmol, 2.36eq) in CH.sub.2Cl.sub.2 (5.0 ml) is added Ac.sub.2O
(1.0 ml). The mixture is stirred at room until the reaction is
complete as judged by mass spectrometry analysis (about 3
hrs).Then, the mixture is diluted with ethyl acetate (50 ml),
washed with water (1.times.30 ml), 1.0 HCl (2.times.20 ml), water
(1.times.20 ml), sat. NaHCO.sub.3 (1.times.20 ml) and brine
(1.times.20 ml), dried with Na.sub.2SO.sub.4, filtered and
evaporated. The crude product is purified by silica gel
chromatography (eluted with 50% ethyl acetate-hexane, then 100%
ethyl acetate) to give diacetate as a white solid. m/e.sup.+ for
C.sub.66H.sub.115N.sub.11O.sub.- 15 1301.86, found 1302.78
(m+H).sup.+, 1319.81 (m+NH.sub.4).sup.+, 1324.77 (m+Na).sup.+.
[0282] Step c. A compound of formula I, wherein Q is 45
[0283] W is Ac and X.dbd.Y=Z=hydrogen.
[0284] A mixture of diacetate (2.0 g, 1.54 mmol), Ph.sub.3P (183
mg, 0.70 mmol), Pd(OAc).sub.2 (73.8 mg, 0.32 mmol) in dioxane (10
ml) is degassed twice and heated at 120.degree. C. The solution
becomes black in about 30 min and the reaction is complete in 1 hr
as judged by mass spectrometry analysis. Solvent is evaporated and
the crude product is purified by silica gel chromatography (eluted
with 50% ethyl acetate-hexane, then 100% ethyl acetate) to give the
title compound product as a light yellow solid. m/e.sup.+ for
C.sub.64H.sub.111N.sub.11O.sub.13 1241.84, found 1242.97
(m+H).sup.+, 1260.00 (m+NH.sub.4).sup.+, 1264.96 (m+Na).sup.+.
Example 3
[0285] A compound of formula I, wherein Q is 46
[0286] W is H and X.dbd.Y=Z=hydrogen.
[0287] A solution of diene acetate of Example 2 (100 mg, 0.080
mmol), K.sub.2CO.sub.3 (55 mg, 0.40 mmol) in MeOH (2 ml) is heated
to 50.degree. C. for 2-3 hr. After cooled to room temperature, the
mixture is diluted with ethyl acetate (20 ml), washed with aq.
NH.sub.4Cl and brine, dried with Na.sub.2SO.sub.4 and concentrated.
The crude product is purified by preparative TLC (eluted 100% ethyl
acetate) to give the title compound as a white solid. m/e.sup.+ for
C.sub.62H.sub.109N.sub.11O.sub.12 1199.82, found 1200.89
(m+H).sup.+, 1222.87 (m+Na).sup.+.
Example 4
[0288] A compound of formula I, wherein Q is 47
[0289] Y is CH.sub.3, and W.dbd.X=Z=hydrogen.
[0290] Step a. A compound of formula 1, wherein A is of the formula
(2-2), Y is CH.sub.3, and X=Z=hydrogen.
[0291] To a solution of cyclosporine adehyde of Example 1 (995 mg,
0.80 mmol) in THF (3 ml) at -78.degree. C. is added a solution of
1-propenylmagnesium bromide (18 ml, 0.5 M in THF). After addition,
the mixture is stirred for 20-30 min and quenched with aq.
NH.sub.4Cl at -78.degree. C. After warm up to room temperature, the
mixture is diluted with ethyl acetate (50 ml), washed with sat
NH.sub.4Cl (30 ml), brine (30 ml), dried with Na.sub.2SO.sub.4,
concentrated and dried by lyophilization to afford a light yellow
solid. m/e.sup.+ for C.sub.65H.sub.115N.sub.11O.sub.14 1273.86,
found 1274.95 (m+H).sup.+, 1291.85 (m+NH.sub.4).sup.+, 1296.85
(m+Na).sup.+.
[0292] Step b. A compound of formula I, wherein A is of the formula
(2-3), Y is CH.sub.3, and X=Z=hydrogen.
[0293] To a solution of cyclosporine A allyl alcohol of Step a (90
mg, 0.071 mmol), DMAP (50 mg), and Py (0.50 ml) in CH.sub.2Cl.sub.2
(0.5 ml) at room is added Ac.sub.2O (0.2 ml). The mixture is
stirred at room until the reaction is complete as judged by mass
spectrometry analysis (about 3 hrs). Then, the mixture is diluted
with ethyl acetate (20 ml), washed with 1.0 HCl (10 ml), water (10
ml), sat. NaHCO.sub.3 (10 ml) and brine (10 ml), dried with
Na.sub.2SO.sub.4, filtered and evaporated. The crude product is
purified by preparative TLC (eluted 100% ethyl acetate) to give the
diacetate compound of Step c as a white solid. m/e.sup.+ for
C.sub.67H.sub.117N.sub.11O.sub.15 1315.87, found 1316.87
(m+H).sup.+, 1333.90 (m+NH.sub.4).sup.+, 1338.85 (m+Na).sup.+.
[0294] Step c. A compound of formula I, wherein Q is 48
[0295] Y is CH.sub.3, and W.dbd.X=Z=hydrogen.
[0296] A mixture of diacetate (240 mg, 0.182 mmol), Ph.sub.3P (31
mg, 0.118 mmol), Pd(OAc).sub.2 (7.1 mg, 0.0316 mmol) in dioxane (2
ml) is degassed twice and heated at 120.degree. C. The solution
became black in about 30 min and the reaction is continued
overnight. Mass spectrometry analysis indicated that the reaction
is not complete. Solvent is evaporated and the product is separated
from the starting material by preparative TLC (eluted with 100%
ethyl acetate). The product (contained triphenylphosphene
by-product) is dissolved in MeOH and stirred with K.sub.2CO.sub.3
(75 mg, 3 eq.) under 50.degree. C. for 3 hrs. After removal of MeOH
by evaporation, the residue is dissolved in ethyl acetate and
filtered through a short silica gel pad. The filtrate is
concentrated and the crude product is purified by preparative TLC
(eluted with 100% ethyl acetate) to give the title compound.
m/e.sup.+ for C.sub.63H.sub.111N.sub.11O.sub.12 1213.84, found
1214.84 (m+H).sup.+, 1236.84 (m+Na).
Example 5
[0297] A compound of formula I, wherein Q is 49
[0298] Y=Z=CH.sub.3, and W.dbd.X=hydrogen.
[0299] Step a. A compound of formula I, wherein A is of the formula
(2-2), Y=Z=CH.sub.3, and X=hydrogen.
[0300] To a solution of cyclosporine adehyde of Example 1 (150 mg,
0.12 mmol) in THF (3 ml) at -78.degree. C. is added a solution of
2-methyl-1-propenylmagnesium bromide (2.4 ml, 0.5 M in THF). After
addition, the mixture is stirred for 20-30 min and quenched with
aq. NH.sub.4Cl at -78.degree. C. After warm up to room temperature,
the mixture is diluted with ethyl acetate (50 ml), washed with sat.
NH.sub.4Cl (30 ml), brine (30 ml), dried with Na.sub.2SO.sub.4,
concentrated and dried by lyophilization to afford a light yellow
solid. m/e.sup.+ for C.sub.66H.sub.117N.sub.11O.sub.14 1287.88,
found 1288.87 (m+H).sup.+, 1310.87 (m+Na).sup.+.
[0301] Step b. A compound of formula I, wherein A is of the formula
(2-3), Y=Z=CH.sub.3, and X=hydrogen.
[0302] To a solution of cyclosporine A allyl alcohol of Step a (90
mg, 0.071 mmol), DMAP (50 mg), and Py (0.50 ml) in CH.sub.2Cl.sub.2
(0.5 ml) at room is added Ac.sub.2O (0.2 ml). The mixture is
stirred at room until the reaction is complete as judged by mass
spectrometry analysis (about 3 hrs).Then, the mixture is diluted
with ethyl acetate (20 ml), washed with 1.0 HCl (10 ml), water (10
ml), sat. NaHCO.sub.3 (10 ml) and brine (10 ml), dried with
Na.sub.2SO.sub.4, filtered and evaporated. The crude product is
purified by preparative TLC (eluted 100% ethyl acetate) to give the
diacetate compound of Step c as a white solid. m/e.sup.+ for
C.sub.68H.sub.119N.sub.11O.sub.15 1329.89, found 1330.66
(m+H).sup.+, 1347.68 (m+NH.sub.4).sup.+, 1352.66 (m+Na).sup.+.
[0303] Step c. A compound of formula I, wherein Q is 50
[0304] Y=Z=CH.sub.3, and X.dbd.W=hydrogen.
[0305] A mixture of diacetate formed in Step b and Ph.sub.3P (31
mg), Pd(OAc).sub.2 (12.71 mg, in dioxane (2 ml) is degassed twice
and heated at 120.degree. C. The solution became black in about 30
min and the reaction is continued overnight. Mass spectrometry
analysis indicated that the reaction is not complete. Solvent is
evaporated and the product is separated from the starting material
by preparative TLC (eluted with 100% ethyl acetate). The product
(contained triphenylphosphene by-product) is dissolved in MeOH and
stirred with K.sub.2CO.sub.3 (75 mg, 3 eq.) under 50.degree. C. for
3 hrs. After removal of MeOH by evaporation, the residue is
dissolved in ethyl acetate and filtered through a short silica gel
pad. The filtrate is concentrated and the crude product is purified
by preparative TLC (eluted with 100% ethyl acetate) to give the
title compound. m/e.sup.+ for C.sub.64H.sub.113N.sub.11O.sub.12
1227.86, found 1228.86(m+H).sup.+, 1250.82 (m+Na).sup.+.
Example 6
[0306] A compound of formula I, wherein Q is 51
[0307] Y is --(CH.sub.2).sub.3CH.sub.3, and W.dbd.X=Z=hydrogen.
[0308] A solution of diene acetate from Example 2 (56 mg, 0.045
mmol), 1-hexene (0.05 ml, 0.594 mmol) and Hoveyda-Grubbs' catalyst
(21 mg, 0.033 mmol) in CH.sub.2Cl.sub.2 (2.0 ml) is degassed twice
and then heated under N.sub.2 at 45.degree. C. overnight. After
cooling to room temperature, solvent is removed and the product is
purified by preparative TLC (developed with 100% ethyl acetate).
m/e.sup.+ for C.sub.68H.sub.119N.sub.11O.sub.13 1297.90, found
1298.92 (m+H).sup.+, 1315.96 (m+NH.sub.4).sup.+, 1320.91
(m+Na).sup.+, H-NMR, C-NMR and DEPT experiments indicated one diene
isomer (>90%) is formed. The acetyl protection group is removed
by stirring with K.sub.2CO.sub.3 (12.9 mg) in MeOH (2 ml) over
night. After removal of methanol, the residue is dissolved in ethyl
acetate and filtered through a short silica gel pad. Evaporation of
solvent provided the title compound diene alcohol. m/e.sup.+ for
C.sub.66H.sub.117N.sub.11O.sub.12 1255.89, found 1256.93
(m+H).sup.+, 1278.91 (m+Na).sup.+.
Example 7
[0309] A compound of formula I, wherein Q is 52
[0310] Y is --(CH.sub.2)Br, and W.dbd.X=Z=hydrogen.
[0311] A solution of diene acetate from Example 2 (56 mg, 0.045
mmol), 4-bromo-but-1-ene (0.05 ml,) and Hoveyda-Grubbs' catalyst
(17.7 mg) in CH.sub.2Cl.sub.2 (2.0 ml) is heated under N.sub.2 at
49.degree. C. overnight. Mass spectrometry analysis indicated that
the reaction is complete. After cooling to room temperature,
solvent is removed and the product is purified by preparative TLC
(developed with 100% ethyl acetate. m/e.sup.+ for
C.sub.66H.sub.114BrN.sub.11O.sub.13 1347.78, found 1348,66,
1349.66, 1350.66, 1351.65 (m+H).sup.+, 1365.68, 1366.68, 1367.69,
1368.69 (m+NH.sub.4).sup.+, 1370.66, 1371.66, 1372.65, 1373.65
(m+Na).sup.+. H-NMR analysis indicated one diene isomer (>90%)
is formed. The acetyl protection group is removed by stirring with
K.sub.2CO.sub.3 (12.9 mg) in MeOH (2 ml) over night. After removal
of methanol, the residue is dissolved in ethyl acetate and filtered
through a short silica gel pad. Evaporation of solvent provided the
title compound diene alcohol. m/e.sup.+ for
C.sub.66H.sub.114BrN.sub.11O.sub.13 1347.78, found 1348,66,
1349.66, 1350.66, 1351.65 (m+H).sup.+, 1365.68, 1366.68, 1367.69,
1368.69 (m+NH.sub.4).sup.+, 1370.66, 1371.66, 1372.65, 1373.65
(m+Na).sup.+.
Example 8
[0312] A compound of formula I, wherein Q is 53
[0313] Y is ortho-Me-phenyl, and W.dbd.X=Z=hydrogen.
[0314] A solution of diene acetate from Example 2 (47.8 mg),
ortho-methylstyrene (0.05 ml,) and Hoveyda-Grubbs' catalyst (2.7
mg) in CH.sub.2Cl.sub.2 (2.0 ml) is heated under N.sub.2 at
45.degree. C. overnight. Mass spectrometry analysis indicats that
the reaction is complete. After cooling to room temperature,
solvent is removed and the product is purified by preparative TLC
(developed with 100% ethyl acetate. m/e.sup.+ for
C.sub.71H.sub.117N.sub.11O.sub.13 1331.88, found 1332.84
(m+H).sup.+, 1349.86 (m+NH.sub.4).sup.+, 1354.82 (m+Na).sup.+. The
acetyl protection group is removed by stirring with K.sub.2CO.sub.3
(12.9 mg) in MeOH (2 ml) over night. After removal of methanol, the
residue is dissolved in ethyl acetate and filtered through a short
silica gel pad. The crude product is purified by preparative TLC
(developed with ethyl acetate). m/e.sup.+ for
C.sub.69H.sub.115N.sub.11O.sub.12 1289.87, found 1290.68
(m+H).sup.+, 1312.66 (m+Na).sup.+.
Example 9
[0315] A compound of formula I, wherein Q is 54
[0316] Y is ortho-Br-phenyl, and W.dbd.X=Z=hydrogen.
[0317] A solution of diene acetate from Example 2 (28 mg),
orthobromostyrene (20 ml) and Hoveyda-Grubbs' catalyst (1.4 mg) in
CH.sub.2Cl.sub.2 (2.0 ml) is heated under N.sub.2 at 45.degree. C.
overnight. Mass spectrometry analysis indicated that the reaction
is complete. After cooling to room temperature, solvent is removed
and the product is purified by preparative TLC (developed with 100%
ethyl acetate. The acetyl protection group is removed by stirring
with K.sub.2CO.sub.3 (12.9 mg) in MeOH (2 ml) over night. After
removal of methanol, the residue is dissolved in ethyl acetate and
filtered through a short silica gel pad. The crude product is
purified by preparative TLC (developed with ethyl acetate).
m/e.sup.+ for C.sub.68H.sub.112BrN.sub.11- O.sub.12 1355.59, found
1378.54 (m+Na).sup.+.
Example 10
[0318] A compound of formula I, wherein Q is 55
[0319] Y is --CO.sub.2Me, and W.dbd.X=Z=hydrogen.
[0320] A solution of diene acetate from Example 2 (27.5 mg),
dimethylmaleate (32.8 mg) and Nolan catalyst (2.7 mg) in
CH.sub.2Cl.sub.2 (2.0 ml) is cooled to -78.degree. C. Then the
mixture is heated under N.sub.2 at 50.degree. C. overnight. Mass
spectrometry analysis indicated that the reaction is complete.
After cooling to room temperature, solvent is removed and the
product is purified by preparative TLC (developed with 100% ethyl
acetate. m/e.sup.+ for C.sub.66H.sub.113N.sub.11O.sub.15 1299.84,
found 1300.80 (m+H).sup.+, 1317.84 (m+NH.sub.4).sup.+, 1322.81
(m+Na).sup.+. The acetyl protection group is removed by stirring
with K.sub.2CO.sub.3 (12.9 mg) in MeOH (2 ml) over night. After
removal of methanol, the residue is dissolved in ethyl acetate and
filtered through a short silica gel pad. The crude product is
purified by preparative TLC (developed with ethyl acetate).
m/e.sup.+ for C.sub.64H.sub.111N.sub.11O.- sub.124 1257.83, found
1296.58 (m+K).sup.+, 1283.61 (m+Na).sup.+.
Example 11
[0321] A compound of formula I, wherein Q is 56
[0322] Y is meta-CHO-phenyl, and W.dbd.X=Z=hydrogen.
[0323] A solution of diene acetate from Example 2 (28 mg),
3-vinylbenzaldehyde (0.015 ml,) and Hoveyda-Grubbs' catalyst (1.4
mg) in CH.sub.2Cl.sub.2 (2.0 ml) is heated under N.sub.2 at
45.degree. C. overnight. Mass spectrometry analysis indicated that
the reaction is complete. After cooling to room temperature,
solvent is removed and the product is purified by preparative TLC
(developed with 100% ethyl acetate. m/e.sup.+ for
C.sub.71H.sub.115N.sub.11O.sub.14 1345.86, found 1346.70
(m+H).sup.+, 1368.69 (m+Na).sup.+. The acetyl protection group is
removed by stirring with K.sub.2CO.sub.3 (12.9 mg) in MeOH (2 ml)
over night. After removal of methanol, the residue is dissolved in
ethyl acetate and filtered through a short silica gel pad. The
crude product is purified by preparative TLC (developed with ethyl
acetate). m/e.sup.+ for C.sub.69H.sub.113N.sub.11O.sub.3 1303.85,
found 1304.66 (m+H).sup.+, 1326.65 (m+Na).sup.+, 1342.62
(m+K).sup.+.
Example 12
[0324] A compound of formula I, wherein Q is 57
[0325] Y is Et, and W.dbd.X=Z=hydrogen
[0326] A solution of diene acetate from Example 2 (43 mg),
3-hexene(cis, trans-mixture) (0.10 ml,) and Hoveyda-Grubbs'
catalyst (2.5 mg) in CH.sub.2Cl.sub.2 (1.0 ml) is heated under
N.sub.2 at 45.degree. C. overnight. Mass spectrometry analysis
indicates that the reaction is complete. After cooling to room
temperature, solvent is removed and the product is purified by
preparative TLC (Whatman, PK5F, Silica gel, 150 A, with fluorescent
indicator, 500 .mu.M thickness, developed with 100% ethyl acetate).
m/e.sup.+ for C.sub.66H.sub.115N.sub.11O.sub.13 1269.87, found
1270.73 (m+H).sup.+, 1287.76 (m+NH.sub.4).sup.+, 1292.72
(m+Na).sup.+. The acetyl protection group is removed by stirring
with K.sub.2CO.sub.3 (12.9 mg) in MeOH (2 ml) at 50.degree. C. for
1 hr. After removal of methanol, the residue is dissolved in ethyl
acetate and filtered through a short silica gel pad. The crude
product is purified by preparative TLC (developed with ethyl
acetate). m/e.sup.+ for C.sub.64H.sub.113N.sub.11O.sub.12 1227.86,
found 1228.84 (m+H).sup.+, 1250.86 (m+Na).sup.+, 1266.85
(m+K).sup.+.
Example 13
[0327] A compound of formula I, wherein Q is 58
[0328] Y is --CH.dbd.CHCH.sub.2TMS, and W.dbd.X=Z=hydrogen
[0329] A solution of diene acetate from Example 2 (68 mg),
allyltrimethylsilane (0.10 ml,) and Hoveyda-Grubbs' catalyst (3.5
mg) in CH.sub.2Cl.sub.2 (1.0 ml) is heated under N.sub.2 at
45.degree. C. overnight. Mass spectrometry analysis indicated that
the reaction is complete. After cooling to room temperature,
solvent is removed and the product is purified by preparative TLC
(Whatman, PK5F, Silica gel, 150 A, with fluorescent indicator, 500
.mu.M thickness, developed with 100% ethyl acetate). m/e.sup.+ for
C.sub.68H.sub.121N.sub.11O.sub.13Si 1327.89, found 1328.88
(m+H).sup.+, 1345.88 (m+NH.sub.4).sup.+, 1350.88 (m+Na).sup.+. The
acetyl protection group is removed by stirring with K.sub.2CO.sub.3
(12.9 mg) in MeOH (2 ml) at 50.degree. C. for 1 hr. After removal
of methanol, the residue is dissolved in ethyl acetate and filtered
through a short silica gel pad. The crude product is purified by
preparative TLC (developed with ethyl acetate). m/e.sup.+ for
C.sub.66H.sub.119N.sub.11O.sub.12Si 1285.88, found 1286.76
(m+H).sup.+, 1303.xx (m+NH.sub.4).sup.+, 1308.80 (m+Na).sup.+,
1324.84 (m+K).sup.+.
Example 14
[0330] A compound of formula I, wherein Q is 59
[0331] G is H, and W is H.
[0332] Step a. A compound of formula I, wherein A is of the formula
(4-2), G=TMS, and W.dbd.Ac
[0333] To a solution n-BuLi (0.65 ml, 2.5 M/THF) in THF (2 ml) at
-78.degree. C. is added trimethylsilylacetylene (0.25 ml). The
mixture is stirred for 10 min and a solution of cyclosporine
adehyde of Example 1 (222mg, 0.18 mmol) in THF (1 ml) is added.
After addition, the mixture is stirred for 20-30 min and quenched
with aq. NH.sub.4Cl at -78.degree. C. After warming to room
temperature, the mixture is diluted with ethyl acetate (50 ml),
washed with sat. NH.sub.4Cl (30 ml), brine (30 ml), dried with
Na.sub.2SO.sub.4, concentrated and dried by lyophilization.
m/e.sup.+ for C.sub.67H.sub.119N.sub.11O.sub.14Si 1329.87, found
1330,87 (m+H).sup.+, 1347.85 (m+NH.sub.4).sup.+,
1352.87(m+Na).sup.+.
[0334] Steb b. A compound of formula I, wherein A is of the formula
(4-4), G=TMS, and W.dbd.Ac
[0335] To solution of the crude product from step a (100 mg) in
CH.sub.2Cl.sub.2 (2 ml) at 0.degree. C. is added 2,6-lutidine (0.2
ml) and triflic anhydride (0.10 ml). The mixture is stirred at
0.degree. C. for 10 min. The mixture is diluted with ethyl acetate
(20 ml), washed with brine and dried with Na2SO4. The crude product
is purified by preparative TLC (developed with ethyl acetate).
m/e.sup.+ for C.sub.67H.sub.117N.sub.11O.sub.13Si 1311.86, found
1313.04 (m+H).sup.+, 1330.06 (m+NH.sub.4).sup.+, 1335.03
(m+Na).sup.+.
[0336] Step c. A compound of formula I, wherein Q is 60
[0337] G is H, and W is H.
[0338] The product from step c is heated with K.sub.2CO.sub.3 (20
mg) in MeOH (2 ml) at 50.degree. C. for 1 hr. After cooling to room
temperature, the solvent is removed and subsequently the residue is
dissolved in ethyl acetate, washed with brine and dried with
Na.sub.2SO.sub.4. The crude product is purified by preparative TLC
(developed with ethyl acetate). m/e.sup.+ for
C.sub.62H.sub.107N.sub.11O.sub.12 1197.81, found 1199.04
(m+H).sup.+, 1217.07 (m+NH.sub.4).sup.+, 1221.01 (m+Na).sup.+.
[0339] Other representative compounds of the present invention
which may be prepared via the synthetic routes delineated herein
include, but are not limited to, Examples 15-27:
Example 15
[0340] A compound of formula I, wherein Q is 61
[0341] Y is propyl, and W.dbd.X=Z=hydrogen.
Example 16
[0342] A compound of formula I, wherein Q is 62
[0343] is cyclopropyl, and W.dbd.X=Z=hydrogen.
Example 17
[0344] A compound of formula I, wherein Q is 63
[0345] Y is --CH.dbd.CHCH.sub.3, and W.dbd.X=Z=hydrogen.
Example 18
[0346] A compound of formula I, wherein Q is 64
[0347] X.dbd.Y.dbd.CH.sub.3, and W=Z=hydrogen.
Example 19
[0348] A compound of formula I, wherein Q is 65
[0349] W.dbd.X.dbd.Y=hydrogen, and Z=CH.sub.3.
Example 20
[0350] A compound of formula I, wherein Q is 66
[0351] Y is p-bromophenyl, and W.dbd.X=Z=hydrogen.
Example 21
[0352] A compound of formula I, wherein Q is 67
[0353] W.dbd.X.dbd.Y=hydrogen, and Z=--CH.sub.2CH.dbd.CH.sub.2.
Example 22
[0354] A compound of formula I, wherein Q is 68
[0355] W.dbd.X.dbd.Y=hydrogen, and Z is ethyl.
Example 23
[0356] A compound of formula I, wherein Q is 69
[0357] W.dbd.X.dbd.Y=hydrogen, and Z=--CH.dbd.CHCH.sub.3.
Example 24
[0358] A compound of formula I, wherein Q is 70
[0359] W.dbd.X.dbd.Y=hydrogen, and Z=--CH.sub.2OCH.sub.3.
Example 25
[0360] A compound of formula I, wherein Q is 71
[0361] G=--CH.dbd.CHCH.sub.3 and W=hydrogen.
Example 26
[0362] A compound of formula I, wherein Q is 72
[0363] G=propyl and W=hydrogen.
Example 27
[0364] A compound of formula I, wherein Q is 73
[0365] G=--CH.sub.3 and W=hydrogen.
[0366] Although the invention has been described with respect to
various preferred embodiments, it is not intended to be limited
thereto, but rather those skilled in the art will recognize that
variations and modifications may be made therein which are within
the spirit of the invention and the scope of the appended
claims.
* * * * *