U.S. patent application number 14/439585 was filed with the patent office on 2015-10-01 for methods and compositions for treating vasomotor symptoms.
The applicant listed for this patent is UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION. Invention is credited to Charles Chavkin, Donald K. Clifton, Victor Navarro, Susan Reed, Robert A. Steiner.
Application Number | 20150272927 14/439585 |
Document ID | / |
Family ID | 49887224 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150272927 |
Kind Code |
A1 |
Steiner; Robert A. ; et
al. |
October 1, 2015 |
METHODS AND COMPOSITIONS FOR TREATING VASOMOTOR SYMPTOMS
Abstract
The present disclosure is generally directed to compositions and
methods for treating or limiting development of vasomotor symptoms
in a subject.
Inventors: |
Steiner; Robert A.;
(Seattle, WA) ; Chavkin; Charles; (Seattle,
WA) ; Clifton; Donald K.; (Seattle, WA) ;
Reed; Susan; (Seattle, WA) ; Navarro; Victor;
(Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR
COMMERCIALIZATION |
Seattle |
WA |
US |
|
|
Family ID: |
49887224 |
Appl. No.: |
14/439585 |
Filed: |
December 3, 2013 |
PCT Filed: |
December 3, 2013 |
PCT NO: |
PCT/US2013/072772 |
371 Date: |
April 29, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61732586 |
Dec 3, 2012 |
|
|
|
Current U.S.
Class: |
514/282 ;
514/428 |
Current CPC
Class: |
A61K 31/485 20130101;
A61K 31/439 20130101; A61K 31/40 20130101; A61K 45/06 20130101;
A61K 31/47 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 31/485 20060101 A61K031/485; A61K 31/439 20060101
A61K031/439 |
Claims
1. A method for treating or limiting development of vasomotor
symptoms (VMS), comprising administering to a subject in need
thereof an amount effective to treat or limit development of VMS of
a compound that inhibits kisspeptin/neurokinin B/dynorphin (KNDy)
neurons.
2. The method of claim 1, wherein the compound is a kappa receptor
agonist.
3. The method of claim 1 wherein the compound comprises a
neurokinin 3 receptor (NK3R) antagonist and/or a neurokinin 1
receptor (NK1R) antagonist.
4. A method for treating or limiting development of VMS, comprising
administering to a subject in need thereof an amount effective to
treat or limit development of VMS of a compound selected from the
group consisting of a kappa agonist, an NK3R antagonist, an NK1R
antagonist, combinations thereof, and pharmaceutically acceptable
salts thereof.
5. The method of claim 1, wherein the kappa receptor agonist is
selected from the group consisting of dynorphin A, (-) U50,488, ICI
199,441, ICI 204,448, Asimadoline, Bremazocine, BRL 52537,
.beta.-NNTA, Enadoline, FE 200665, Fedotozine, 6' GNTI, GR89696,
HZ-2, Ketocyclazocine, Levallorphan, LPK-26, Nalfurafine HCl,
N-Methyl-N-(7-(1-pyrolidinyl)-1-oxaspiro(4,5)dec-8-yl)-4-benzofuranacetam-
ide, N-MPPP Hydrochloride, (-) Pentazocine, (+) Pentazocine,
Salvinorin, Salvinorin B, Tifluadom, Cara Therapeutics compound
CR854, Spiradoline, U-69593, U62066, a peptide having the following
general formula: H-Xaa1-Xaa2-Xaa3-Xaa4-substituted amide wherein
Xaa1 is (A)D-Phe, (CMe)D-Phe, D-Tyr, D-Tic or D-Ala(cyclopentyl or
thienyl), with A being H, NO.sub.2, F, Cl or CH.sub.3; Xaa2 is
(A')D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, with A' being A or
3,4Cl.sub.2 ; Xaa3 is D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe
or D-Ala(cyclopentyl) with B being H or C.sup..alpha.Me; Xaa4 is
D-Arg, D-Har, D-nArg, D-Lys, D-Lys(Ipr), D-Arg(Et.sub.2),
D-Har(Et.sub.2), D-Amf(G), D-Dbu, (B)D-Orn or D-Orn(Ipr), with G
being H or amidino; and Q is NR.sub.1R.sub.2, morpholinyl,
thiomorpholinyl, (C)piperidinyl, piperazinyl, 4-mono- or
4,4-di-substituted piperazinyl or .delta.-ornithinyl, with R.sub.1
being lower alkyl, substituted lower alkyl, benzyl, substituted
benzyl, aminocyclohexyl, 2-thiazolyl, 2-picolyl, 3-picolyl or
4-picolyl, R.sub.2 being H or lower alkyl; and C being H, 4-hydroxy
or 4-oxo; and a compound having the formula: ##STR00103## wherein
each Xaa1 is independently chosen from (A)(A')D-phenylalanine,
(A)(A')(.alpha.-Me)D-phenylalanine, D-tyrosine,
D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid, D-phenylglycine,
D-neopentylglycine, D-homophenylalanine, .beta.-(E)D-Ala and
D-tert-butyl-Gly, wherein (A) and (A') are each phenyl ring
substituents independently chosen from --H, --F, --Cl, --NO.sub.2,
--CH.sub.3, --CF.sub.3, --CN, --CONH.sub.2, and wherein each (E) is
independently chosen from tert-butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and
benzothienyl; each Xaa2 is independently chosen from
(A)(A')D-phenylalanine, (A)(A')(.alpha.-Me)D-phenyl-alanine,
naphthyl-1-D-alanine, naphthyl-2-D-alanine, D-tyrosine,
(E)D-alanine, and D-tryptophan; each Xaa3 is independently chosen
from D-norleucine, D-phenylalanine, (E)D-alanine, D-leucine,
(.alpha.-Me)D-leucine, D-homoleucine, D-valine, and D-methionine;
each Xaa4 is independently chosen from (B)2D-arginine,
(B)2D-norarginine, (B)2D-homoarginine, .zeta.-(B)D-homolysine,
D-2,3-diaminopropionic acid, .epsilon.-(B)D-lysine,
.epsilon.-(B)2-D-lysine, D-(NH2CH2-)phenylalanine,
amidino-D-(NH2CH2-) phenylalanine, .gamma.-(B)2D-diamino butyric
acid, .delta.-(B)2.alpha.-(3')D-ornithine,
D-2-amino-3(4-piperidyl)propionic acid,
D-2-amino-3(2-aminopyrrolidyl)propionic acid,
D-.alpha.-amino-.beta.-amidino-propionic acid,
.alpha.-amino-4-piperidineacetic acid,
cis-.alpha.,4-diaminocyclohexane acetic acid,
trans-.alpha.,4-diaminocyclohexaneacetic acid,
cis-.alpha.-amino-4-methyl-aminocyclo-hexane acetic acid,
trans-.alpha.-amino-4-methylaminocyclohexane acetic acid,
.alpha.-amino-1-amidino-4-piperidineacetic acid,
cis-.alpha.-amino-4-guanidino-cyclohexane acetic acid, and
trans-.alpha.-amino-4-guanidinocyclohexane acetic acid, wherein
each (B) is independently chosen from --H and C1-C4 alkyl, and (B')
is H or (.alpha.-Me); and p is zero or 1; G is selected from one of
the following three moieties: (i) G is ##STR00104## wherein p, q,
r, s and t are each independently zero or 1, provided that at least
one of s and t are 1; and L is a linker chosen from
.epsilon.-D-lysine, .epsilon.-lysine, .delta.-D-ornithine,
.epsilon.-ornithine, .gamma.-amino-butyric acid, 8-aminooctanoic
acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxa-octanoic acid,
4-amino-4-carboxylic piperidine and bis(D-Lys-Gly)Lactam; (ii) G is
##STR00105## and p is 1; and the moiety ##STR00106## is an
optionally substituted 4 to 8-membered heterocyclic ring moiety
wherein Y is C or N and Z is a carbon atom, a nitrogen atom, an
oxygen atom, a sulfur atom, a sulfoxide group, or a sulfonyl group;
provided that when such ring moiety is a 6-, 7- or 8-membered ring,
Y and Z are separated by at least two ring atoms; and provided
further that when such ring moiety is aromatic, then Y is a carbon
atom; and (iii) G is ##STR00107## wherein J is a 5-, 6-, or
7-membered heterocyclic ring moiety comprising 1, 2, or 3
heteroatoms in the ring, wherein R3 and R4 are each independently
selected from H, C1-C3 alkyl, halo, --OH, --CF.sub.3, --NH.sub.2,
--COOH and amidino; and R5 and R6 are each independently chosen
from H, C1-C3 alkyl, oxo, halo, --OH, --CF.sub.3, --NH.sub.2,
--COOH and amidino; wherein W' is chosen from: the moiety
--NH--(CH.sub.2).sub.bwith b equal to zero, 1, 2, 3, 4, 5, or 6;
and the moiety --NH--(CH.sub.2).sub.c--O-- with c equal to 2 or 3.
and stereoisomers, mixture of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, solvates, acid salt
hydrates, N-oxides and isomorphic crystalline forms thereof.
6. The method of claim 2, wherein the kappa receptor agonist is
peripherally restricted.
7. The method of claim 6, wherein the peripherally restricted kappa
receptor agonist is selected from the group consisting of
ICI-204,448, CR845, Asimadoline, FE 200665, and Fedotozine, a
peptide having the following general formula:
H-Xaa1-Xaa2-Xaa3-Xaa4-substituted amide wherein Xaa1 is (A)D-Phe,
(C.sup..alpha.Me)D-Phe, D-Tyr, D-Tic or D-Ala(cyclopentyl or
thienyl), with A being H, NO.sub.2, F, Cl or CH.sub.3; Xaa2 is
(A')D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, with A' being A or
3,4Cl.sub.2; Xaa3 is D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or
D-Ala(cyclopentyl) with B being H or C.sup..alpha.Me; Xaa4 is
D-Arg, D-Har, D-nArg, D-Lys, D-Lys(Ipr), D-Arg(Et.sub.2),
D-Har(Et.sub.2), D-Amf(G), D-Dbu, (B)D-Orn or D-Orn(Ipr), with G
being H or amidino; and Q is NR.sub.1R.sub.2, morpholinyl,
thiomorpholinyl, (C)piperidinyl, piperazinyl, 4-mono- or
4,4-di-substituted piperazinyl or .delta.-ornithinyl, with R.sub.1
being lower alkyl, substituted lower alkyl, benzyl, substituted
benzyl, aminocyclohexyl, 2-thiazolyl, 2-picolyl, 3-picolyl or
4-picolyl, R.sub.2 being H or lower alkyl; and C being H, 4-hydroxy
or 4-oxo; and a compound having the formula: ##STR00108## wherein
each Xaa1 is independently chosen from (A)(A')D-phenylalanine,
(A)(A')(.alpha.-Me)D-phenylalanine, D-tyrosine,
D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid, D-phenylglycine,
D-neopentylglycine, D-homophenylalanine, .beta.-(E)D-Ala and
D-tert-butyl-Gly, wherein (A) and (A') are each phenyl ring
substituents independently chosen from --H, --F, --Cl, --NO.sub.2,
--CH.sub.3, --CF.sub.3, --CN, --CONH.sub.2, and wherein each (E) is
independently chosen from tert-butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and
benzothienyl; each Xaa2 is independently chosen from
(A)(A')D-phenylalanine, (A)(A')(.alpha.-Me)D-phenyl-alanine,
naphthyl-1-D-alanine, naphthyl-2-D-alanine, D-tyrosine,
(E)D-alanine, and D-tryptophan; each Xaa3 is independently chosen
from D-norleucine, D-phenylalanine, (E)D-alanine, D-leucine,
(.alpha.-Me)D-leucine, D-homoleucine, D-valine, and D-methionine;
each Xaa4 is independently chosen from (B)2D-arginine,
(B)2D-norarginine, (B)2D-homoarginine, .zeta.-(B)D-homolysine,
D-2,3-diaminopropionic acid, .epsilon.-(B)D-lysine,
.epsilon.-(B)2-D-lysine, D-(NH2CH2-)phenylalanine,
amidino-D-(NH2CH2-) phenylalanine, .gamma.-(B)2D-diamino butyric
acid, .delta.-(B)2.alpha.-(B')D-ornithine,
D-2-amino-3(4-piperidyl)propionic acid,
D-2-amino-3(2-aminopyrrolidyl)propionic acid,
D-.alpha.-amino-.beta.-amidino-propionic acid,
.alpha.-amino-4-piperidineacetic acid,
cis-.alpha.,4-diaminocyclohexane acetic acid,
trans-.alpha.,4-diaminocyclohexaneacetic acid,
cis-.alpha.-amino-4-methyl-aminocyclo-hexane acetic acid,
trans-.alpha.-amino-4-methylaminocyclohexane acetic acid,
.alpha.-amino-1-amidino-4-piperidineacetic acid,
cis-.alpha.-amino-4-guanidino-cyclohexane acetic acid, and
trans-.alpha.-amino-4-guanidinocyclohexane acetic acid, wherein
each (B) is independently chosen from --H and C1-C4 alkyl, and (B')
is --H or (.alpha.-Me); and p is zero or 1; G is selected from one
of the following three moieties: (i) G is ##STR00109## wherein p,
q, r, s and t are each independently zero or 1, provided that at
least one of s and t are 1; and L is a linker chosen from
.epsilon.-D-lysine, .epsilon.-lysine, .delta.-D-ornithine,
.epsilon.-ornithine, .gamma.-amino-butyric acid, 8-aminooctanoic
acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxa-octanoic acid,
4-amino-4-carboxylic piperidine and bis(D-Lys-Gly)Lactam; (ii) G is
##STR00110## and p is 1; and the moiety ##STR00111## is an
optionally substituted 4 to 8-membered heterocyclic ring moiety
wherein Y is C or N and Z is a carbon atom, a nitrogen atom, an
oxygen atom, a sulfur atom, a sulfoxide group, or a sulfonyl group;
provided that when such ring moiety is a 6-, 7- or 8-membered ring,
Y and Z are separated by at least two ring atoms; and provided
further that when such ring moiety is aromatic, then Y is a carbon
atom; and (iii) G is ##STR00112## wherein J is a 5-, 6-, or
7-membered heterocyclic ring moiety comprising 1, 2, or 3
heteroatoms in the ring, wherein R3 and R4 are each independently
selected from H, C1-C3 alkyl, halo, --OH, --CF.sub.3, --NH.sub.2,
--COOH and amidino; and R5 and R6 are each independently chosen
from H, C1-C3 alkyl, oxo, halo, --OH, --CF.sub.3, --NH.sub.2,
--COOH and amidino; wherein W' is chosen from: the moiety
--NH--(CH.sub.2).sub.b-- with b equal to zero, 1, 2, 3, 4, 5, or 6;
and the moiety --NH--(CH.sub.2).sub.c--O-- with c equal to 2 or 3,
and stereoisomers, mixture of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, solvates, acid salt
hydrates, N-oxides and isomorphic crystalline forms thereof.
8. The method of claim 1 wherein the compound comprises a
neurokinin type 3 receptor (NK3R) antagonist.
9. The method of claim 8, wherein the NK3R antagonist is selected
from the group consisting of SB222200, SR 142801, SB 218795, SSR
146977 HCl, AZD2624, Talnetant, and stereoisomers, mixture of
stereoisomers, prodrugs, pharmaceutically acceptable salts,
hydrates, solvates, acid salt hydrates, N-oxides and isomorphic
crystalline forms thereof.
10. The method of claim 1 wherein the compound comprises a
neurokinin type 1 receptor (NK1R) antagonist.
11. The method of claim 10, wherein the NKR1 antagonist is selected
from the group consisting of SR140333, L-733,060 hydrochloride, CP
96345, Aprepitant, RP 67580, RPR-100893, CP-122721, CJ-11974;
L-754,274; GR-203040, GR-205171, LY-303870, CP 99994, FK 888, GR
82334, L 760735, L-732,138; SDZ NKT 343; Spantide I, and
stereoisomers, mixture of stereoisomers, prodrugs, pharmaceutically
acceptable salts, hydrates, solvates, acid salt hydrates, N-oxides
and isomorphic crystalline forms thereof.
12. The method of claim 1, wherein the subject is a menopausal or
perimenopausal woman.
13. The method of claim 1, wherein the subject has surgical or
medically-induced VMS.
14. The method of claim 1, wherein treating or limiting development
of VMS comprises decreasing or limiting development of one or more
of flushing of the skin, sweating, palpitations, racing heart rate,
shivering, intermittent feeling of being too hot (hot flashes) or
too cold (chills/shivering), irritability, anxiety, mood disorders,
and depression, in the subject.
15. A pharmaceutical composition, comprising: (1) two or more of a
kappa agonist, an NK3R antagonist, an NK1R antagonist, or salts
thereof; and (2) a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15, wherein the
composition comprises a kappa agonist, and wherein the kappa
agonist is a peripherally restricted kappa agonist.
17. The pharmaceutical composition of claim 15, wherein the
composition comprises a kappa agonist.
18. The pharmaceutical composition of claim 15, wherein the
composition comprises a NK3R antagonist.
19. The pharmaceutical composition of claim 15, wherein the
composition comprises a NK1R antagonist.
Description
CROSS REFERENCE
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 61/732,586 filed Dec. 3, 2012, incorporate by
reference herein in its entirety.
BACKGROUND
[0002] Vasomotor symptoms (VMS), e.g., thermal instability manifest
as hot flashes, chills, night sweats, anxiety, racing heart, facial
flushing, and/or heart palpitations, can greatly impact quality of
life as women transition through menopause or as they experience
declining levels of estradiol following medical or surgical
oophorectomy. VMS can be unpleasant, distressing and debilitating.
Men may also experience VMS as a result of orchiectomy or medical
treatments that acutely suppress testicular function (e.g.,
gonadotropin-releasing hormone [GnRH] antagonists, which act on the
pituitary). Hot flashes and night sweats occur in more than 75% of
women who are transitioning through menopause, and hot flashes and
night sweats are commonly associated with sleep disturbances, mood
changes, heart palpitations, facial skin flushing, and a reduced
quality of life. Menopausal VMS are triggered by a loss of
estrogenic signaling to the brain, following an age-dependent
decline in ovarian function and incipient thermoregulatory
instability. Estrogen therapy (ET) is effective in treating VMS;
however, ET has significant attendant medical risks particularly
for women with a uterus and taking estrogen plus progestin (EPT),
including increased incidence of venous/thromboembolism, breast
cancer, stroke, coronary artery and gall bladder disease. Many
women find such risks unacceptable. Hence, there is a great need to
develop better and safer alternatives to treat VMS and reduce their
negative impact on patients' health and well-being.
SUMMARY OF THE INVENTION
[0003] In a first aspect, the present invention provides methods
for treating or limiting development of vasomotor symptoms (VMS),
comprising administering to a subject in need thereof an amount
effective to treat or limit development of VMS of a compound that
inhibits kisspeptin/neurokinin B/dynorphin (KNDy) neurons. In one
embodiment, the compound is a kappa receptor agonist. In another
embodiment, the compound comprises a a neurokinin 3 receptor (NK3R)
antagonist and/or a neurokinin 1 receptor (NK1R) antagonist.
[0004] In another aspect, the present invention provides methods
for treating or limiting development of VMS, comprising
administering to a subject in need thereof an amount effective to
treat or limit development of VMS of a compound selected from the
group consisting of a kappa agonist, an NK3R antagonist, an NK1R
antagonist, combinations thereof, and pharmaceutically acceptable
salts thereof.
[0005] In one embodiment of either aspect of the methods of the
invention, the subject is a menopausal or perimenopausal woman; in
another embodiment, the subject has surgical or medically-induced
VMS. In various further embodiments, treating or limiting
development of VMS comprises decreasing or limiting development of
one or more of flushing of the skin, sweating, palpitations, racing
heart rate, shivering, intermittent feeling of being too hot (hot
flashes) or too cold (chills/shivering), irritability, anxiety,
mood disorders, and depression, in the subject.
[0006] In another aspect, the invention provides pharmaceutical
compositions, comprising:
[0007] (1) two or more of a kappa agonist, an NK3R antagonist, an
NK1R antagonist, or salts thereof; and
[0008] (2) a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIG. 1 is a graphical representation of the action of
estrogen-sensitive kisspeptin/dynorphin/NKB (KNDy) neurons in the
arcuate nucleus and the thermoregulatory centers (comprising
"warm-sensing" (WS) neurons in the preoptic area (POA)), which
control vasomotor function (and trigger hot flashes). Also shown is
the modulatory input of estrogen-sensitive serotonergic (5HT) and
noradrenergic neurons (NE), which send projections to the POA from
the raphe nuclei and locus coeruleus, respectively.
[0010] FIG. 2 is a graph showing an ICI-induced dose-dependent
decrease in LH secretion in mice, N.B. 1 mg/kg and 10 mg/kg in
different experiment/assay.
[0011] FIG. 3 is a graph showing the effects of an oral
administration of pentazocine plus naloxone (TalwinNx) on the
frequency of hot flashes in menopausal women (measured over a
period of 6 hours following oral ingestion), showing the ability of
a kappa agonist (pentazocine) to inhibit hot flashes.
DETAILED DESCRIPTION OF THE INVENTION
[0012] It must be noted that, as used in the specification, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise.
[0013] Any terms not directly defined herein shall be understood to
have the meanings commonly associated with them as understood
within the art of the present disclosure. Certain terms are
discussed herein to provide additional guidance to the practitioner
in describing the compositions, devices, methods, and the like, of
embodiments of the present disclosure, and how to make or use them.
It will be appreciated that the same thing can be said in more than
one way. Consequently, alternative language and synonyms can be
used for any one or more of the terms discussed herein. No
significance is to be placed upon whether or not a term is
elaborated or discussed herein. Some synonyms or substitutable
methods, materials and the like are provided. Recital of one or a
few synonyms or equivalents does not exclude use of other synonyms
or equivalents, unless it is explicitly stated. Use of examples,
including examples of terms, is for illustrative purposes only and
does not limit the scope and meaning of the embodiments of the
present disclosure herein.
[0014] All embodiments disclosed herein can be used in combination,
unless the context clearly indicates otherwise. Unless the context
clearly requires otherwise, throughout the description and the
claims, the words `comprise`, `comprising`, and the like are to be
construed in an inclusive sense, as opposed to an exclusive or
exhaustive sense; that is to say, in the sense of "including, but
not limited to". Words using the singular or plural number also
include the plural or singular number, respectively. Additionally,
the words "herein," "above" and "below" and words of similar
import, when used in this application, shall refer to this
application as a whole and not to any particular portions of this
application.
[0015] The following description provides specific details for a
thorough understanding of, and enabling description for,
embodiments of the disclosure. However, one skilled in the art will
understand that the disclosure may be practiced without these
details. In other instances, well-known structures and functions
have not been shown or described in detail to avoid unnecessarily
obscuring the description of the embodiments of the disclosure.
Persons skilled in the relevant art can appreciate that many
modifications and variations are possible in light of the
embodiment teachings. Accordingly, the disclosure is intended to be
illustrative, but not limiting, of the scope of invention.
[0016] In a first aspect the present invention provides methods for
treating or limiting development of vasomotor symptoms (VMS),
comprising administering to a subject in need thereof an amount
effective to treat VMS of a compound that inhibits
kisspeptin/neurokinin B/dynorphin (KNDy) neuronal activity. As
disclosed herein, the inventors have discovered that blocking KNDy
neuronal activity (either altering KNDy neuronal activity, or
interfering with the ability of KNDy neurons to communicate with
downstream target cells) serves to treat VMS. While not being bound
by any specific mechanism of action, FIG. 1 illustrates a model of
linkage of KNDy neurons in the arcuate nucleus to thermoregulatory
centers located in the preoptic area (POA) of the hypothalamus. As
illustrated in FIG. 1, the network of KNDy neurons influences the
hypothalamic mechanisms that control thermoregulation. Accordingly,
aspects of the present disclosure are directed to methods and
compositions for the treatment of VMS-associated thermoregulatory
instability.
[0017] The methods of the invention can be used to treat any
suitable subject, such as a human subject (male or female)
suffering from VMS or at risk of developing hot flashes. In one
embodiment, the subject is a menopausal or perimenopausal woman. In
another embodiment, the subject is a subject with medically- or
surgically-induced VMS, or who is at risk of medically- or
surgically-induced VMS (e.g., a subject who has undergone or will
be undergoing a medical or surgical procedure that may cause VMS,
including but not limited to medical or surgical oophorectomy,
orchiectomy or medical treatments that acutely suppress testicular
function (e.g., GnRH antagonists).
[0018] The methods of the invention serve to treat or limit
development of one or more VMS associated with thermal instability
which include, but are not limited to, flushing of the skin
(blushing/reddening), sweating, palpitations, racing heart rate,
heart palpitations, intermittent feeling of being too hot (hot
flashes) or too cold (chills/shivering), sleep disturbances,
irritability, anxiety, depression and mood disorders. VMS as used
throughout this document refers to this definition with one or more
of its concomitant associated symptoms.
[0019] As used herein, "treat" or "treating" means accomplishing
one or more of the following in an individual that is suffering
from VMS: (a) reducing the severity of one or more VMS; (b)
limiting or preventing development of one or more VMS; (c)
inhibiting worsening of one or more VMS; (d) limiting or preventing
one or more VMS recurrence in subjects that have previously had the
disorder(s); and (e) limiting or preventing recurrence of one or
more VMS in patients that previously had VMS.
[0020] As used herein, "limiting" or "limiting development of"0
means accomplishing one or more of the following in an individual
that has not yet experienced VMS: (a) limiting development of one
or more VMS; (b) reducing the severity one or more VMS; and (c)
limiting or preventing development of one or more VMS.
[0021] As used herein, an "amount effective" refers to an amount of
the composition that is effective for treating and/or limiting the
relevant one or more VMS. The effective amount may vary from
subject to subject, depending upon the age, the subject's size and
health, the nature and extent of the condition being treated,
recommendations of the treating physician, and the therapeutics or
combination of therapeutics selected for administration. Thus, the
effective amount for a given situation can be determined by routine
experimentation. For purposes of the present disclosure, generally
a therapeutic amount will be in the range of about 0.01 mg/kg to
about 250 mg/kg body weight, more preferably about 0.1 mg/kg to
about 10 mg/kg, in at least one dose. The subject can be
administered as many doses as is required to treat or limit the hot
flashes.
[0022] Any suitable compounds that can either block KNDy neuronal
activity or interfere with the ability of KNDy neurons to
communicate with other neurons can be used in the methods of the
invention. In non-limiting embodiments, the compounds may be kappa
agonists, including but not restricted to those whose action is
predominantly "peripheral" or outside of the confines the
blood-brain barrier, so-called peripherally-restricted agents, such
as peripherally restricted kappa agonists (PRKAs), neurokinin type
3 receptor (NK3R) antagonists, or neurokinin type 1 receptors
(NK1R) antagonists, combinations thereof, and salts thereof, all of
which can act in the hypothalamus to inhibit KNDy neuron activity
(and potentially VMS related to thermal instability). In a
preferred embodiment, the compound's action is predominantly
"peripheral" or outside of the confines the blood-brain barrier,
and the compounds are referred to as peripherally-restricted
agents.
[0023] Kappa agonists act in the hypothalamus (part of which is
outside of the blood-brain barrier and therefore accessible to
agents that are administered into the "periphery", i.e., by oral,
peripheral intravenous, intraperitoneal, or subcutaneous routes of
administration) to suppress GnRH secretion and inhibit KNDy
neuronal activity (22, 25, 29-32). Accordingly, one embodiment of
the present invention is directed to activating kappa receptor
signaling pathways in the arcuate nucleus--which is outside of the
blood-brain-barrier and accessible to systemically-delivered (even
highly charged) compounds (33-35 and 40-41)--with a
peripherally-restricted kappa agonist (PRKA), thereby reducing or
blocking pulsatile KNDy neuronal activity and thereby ameliorating
VMS. Likewise, other agents that suppress KNDy neuron activity
(such as NK3R or NK1R antagonists, including but not limited to
peripherally restricted antagonists) would inhibit KNDy neuronal
activity and VMS.
[0024] The term "agonist" refers to a compound that can combine
with a kappa receptor to produce or alter (i.e., modulate, inhibit,
activate or induce) cellular activity, so as to mimic the action of
the endogenous, naturally occurring ligand. An agonist may be a
ligand that directly binds to the receptor. Alternatively, an
agonist may combine with a receptor indirectly by, for example, (a)
forming a complex with another molecule that directly binds to the
receptor, or (b) otherwise results in the modification of another
compound so that the other compound directly binds to the kappa
receptor. The term "activate", and variations thereof, refers to
any measurable increase in cellular activity.
[0025] Another aspect of the present invention provides methods for
treating VMS, comprising administering to a subject in need thereof
an amount effective to treat VMS with a kappa agonist, an NK3R
antagonist, an NK1R antagonist, combinations thereof, and
pharmaceutically acceptable salts thereof.
[0026] Any suitable kappa agonists can be used in the methods of
the present invention. In various non-limiting embodiments, the
kappa agonist may comprise or consist of one or more of the
following (or stereoisomers, mixture of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, salts, solvates, acid
salt hydrates, N-oxides and isomorphic crystalline farms
thereof):
[0027] (a) Dynorphin A: (Available from, for example, Tocris
Bioscience);
[0028] (b) (-) U50,488--(Available from Sigma-Aldrich, for
example)
##STR00001##
[0029] (c) ICI 199,441 (Available from, for example, Tocris
Bioscience) Chemical Name:
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-
acetamide hydrochloride (Cat. #0778)
##STR00002##
[0030] (d) ICI 204,448--(Available from, for example, Tocris
Bioscience): Chemical Name:
(RS)-[3-[1-[[(3,4-Dichlorophenyl)acetyl]methylamino]-2-(1-pyrrolidinyl)et-
hyl]phenoxy]acetic acid hydrochloride
##STR00003##
[0031] (e) Asimadoline (EMD-61753)--(Available from, for example,
Tocris Bioscience): Chemical Name:
N-[(1S)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-N-methyl-2,2-dip-
henylacetamide
##STR00004##
[0032] (f) Bremazocine--Chemical names:
6-ethyl-3-[(1-hydroxycyclopropyl)methyl]-11,11-dimethyl-1,2,3,4,5,6-hexah-
ydro-2,6-methano-3-benzazocin-8-ol: also known as
2-(1-hydroxy-cyclopropylmethyl)-5-ethyl-9,9-dimethyl-2'-hydroxy-6,7-benzo-
morphan
##STR00005##
[0033] (g) BRL 52537--(Available from, for example, Tocris
Bioscience):
(.+-.)-1-(3,4-Dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine
hydrochloride (Cat. #0699)
##STR00006##
[0034] (h) .beta.-NNTA
##STR00007##
[0035] (i) Enadoline: Also known as Cam 569; PD 129289;
4-Benzofuranacetamide,
N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl);
N-Methyl-N-(7-(1-pyrolidinyl)-1-oxaspiro(4,5)dec-8-yl)-4-benzofuranacetam-
ide; SureCN220054; AC1L334T; CAM-569; CAM-570; C24H32N2O3;
LS-172051; PD-129289; PD-129290: L000184; 1-Oxaspiro(4,5)decane,
4-benzofuranacetamide deriv;
2-(1-benzofuran-4-yl)-N-methyl-N-(9-pyrrolidin-1-yl-4-oxaspiro[4,5]decan--
8-yl)acetamide; 107431-28-7
##STR00008##
[0036] (j) FE 200665 (CR665)--(Available from, for example, Tocris
Bioscience):
(R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-N-((R-
)-5-guanidino-1-oxo-1-((pyridin-4-ylmethyl)amino)pentan-2-yl)hexanamide;
also known as H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-Picolyl
##STR00009##
[0037] (k)
Fedotozine--(2R)-N,N-dimethyl-2-phenyl-1-[(3,4,5-trimethoxybenz-
yl)oxy]-2-butanamine
##STR00010##
[0038] (l) 6' GNTI--(Available from, for example, Tocris
Bioscience):
5'-Guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5.alpha.-epoxy-3,14-di-
hydroxy-6,7-2',3'-indolomorphinan dihydrochloride
##STR00011##
[0039] (m) GR89696--(Available from, for example, Tocris
Bioscience):
4-[(3,4-Dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarbo-
xylic acid methyl ester fumarate (Cat #1483)
##STR00012##
[0040] (n) HZ-2-Dimethyl
3,7-dimethyl-9-oxo-2,4-dipyridin-2-yl-3,7-diazabicyclo[3.3.1]nonane-1,5-d-
icarboxylate
##STR00013##
[0041] (o) Ketocyclazocine (Available from, for example, Toronto
Research Chemicals)
(2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahy-
dro-2,6-methano-3-benzazocin-1(2H)-one; also known as (-)-Keto
Cyclazocine and Ketazocine
##STR00014##
[0042] p) Levallorphan--(Available from, for example, Sigma
Aldrich): (-)-17-allylmorphinan-3-ol; also known as Lorfan,
naloxiphan, and 17-(2-Propenyl)morphinan-3-ol tartrate
##STR00015##
[0043] (q) LPK-26--(Available from, for example, Sigma Aldrich):
2-(3,4-dichlorophenyl)-N-[(2S)-1-(2,5-dihydropyrrol-1-yl)-3-methylbutan-2-
-yl]-N-methylacetamide; or
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrroliny-
l))ethyl]acetamide hydrochloride
##STR00016##
[0044] (r) Nalfurafine HCl:
(2E)-N-[(5.alpha.,6.beta.)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epox-
ymorphinan-6-yl]-3-(3-furyl)-N-methylacrylamide
##STR00017##
[0045] (s)
N-Methyl-N-(7-(1-pyrolidinyl)-1-oxaspiro(4,5)dec-8-yl)-4-benzof-
uranacetamide
[0046] (t) N-MPPP Hydrochloride (Available from, for example,
Tocris Bioscience):
N-Methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]phenylacetamide
hydrochloride (Cat. #0783)
##STR00018##
[0047] (-) Pentazocine--(Available from, for example, Sigma
Aldrich)
##STR00019##
[0048] (v) (+) Pentazocine--(Available from, for example, Sigma
Aldrich)
##STR00020##
[0049] Both versions of Pentazocine (u and v) are also known as:
Pentazocaine, Liticon, Pentagin, Pentazocin, Soseton, Talwan,
Fortral, Fortalgesic, or Fortalin;
[0050] (w) Salvinorin A (Available from, for example, Tocris
Bioscience):
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Acetyloxy)-2-(3-furanyl)dodecahydro-6a,10-
b-dimethyl-4,10-dioxo-2H-naphtho[2,1-c]pyran-7-carboxylic acid
methyl ester
##STR00021##
[0051] (x) Salvinorin B--(Available from, for example,
Sigma-Aldrich):
(2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-Furanyl)dodecahydro-9-hydroxy-6a,10b-di-
methyl-4,10-dioxo 2H-naphtho[2.1-c]pyran-7-carboxylic acid methyl
ester
##STR00022##
[0052] (y) Tifluadom (Available from, for example, Toronto research
Chemicals):
N-[(5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1,4-benzodiazepin-2-yl)methyl-
]thiophene-3-carboxamide
##STR00023##
[0053] (z) Spiradoline (U-62066) (Available from, for example,
Sigma Aldrich):
2-(3,4-dichlorophenyl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-
-1-oxaspiro[4.5]decan-8-yl]
##STR00024##
[0054] (aa) U-69593--(Available from, for example, Sigma Aldrich):
(+)-(5.alpha.,7.alpha.,8.beta.)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-
[4.5}dec-8-yl}-benzeneacetamide
##STR00025##
[0055] (bb) U62066--(Available from for example, Sigma Aldrich):
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-Dichloro-N-methyl-N-[7-(1-pyrrolid-
inyl)-1-oxaspiro[4.5]dec-8-yl]benze
##STR00026##
[0056] (cc) One or more peptides as disclosed in U.S. Pat. No.
5,965,701 that exhibit high selectivity for the kappa receptor,
long duration of in vivo action, and do not exhibit any significant
brain penetration (e.g., peripherally restricted. These peptides
comprise a sequence of four D-isomer amino acids having a
C-terminus that is either mono- or di-substituted amide, and have
the following general formula:
H-Xaa1-Xaa2-Xaa3-Xaa4-substituted amide:
[0057] wherein Xaa1 is (A)D-Phe, (C.sup..alpha.Me)D-Phe, D-Tyr,
D-Tic or D-Ala(cyclopentyl or thienyl), with A being H, NO.sub.2,
F, Cl or CH.sub.3; Xaa2 is (A')D-Phe, D-1Nal, D-2Nal, D-Tyr or
D-Trp, with A' being A or 3.4Cl.sub.2; Xaa3 is D-Nle, (B) D-Leu,
D-Hle, D-Met, D-Val, or D-Ala(cyclopentyl) with B being H or
C.sup..alpha.Me; Xaa4 is D-Arg, D-Har, D-nArg, D-Lys, D-Lys(Ipr),
D-Arg(Et.sub.2), D-Har(Et.sub.2), D-Amf(G), D-Dbu, (B)D-Om or
D-Om(Ipr), with G being H or amidino; and Q is NR.sub.1 R.sub.2,
morpholinyl, thiomorpholinyl, (C) piperidinyl, piperazinyl, 4-mono-
or 4,4-di-substituted piperazinyl or .delta.-ornithinyl, with
R.sub.1 being lower alkyl, substituted lower alkyl, benzyl,
substituted benzyl, aminocyclohexyl, 2-thiazolyl, 2-picolyl,
3-picolyl or 4-picolyl, R.sub.2 being H or lower alkyl; and C being
H, 4-hydroxy or 4-oxo.
[0058] For purposes of the compounds of (cc), as disclosed in U.S.
Pat. No. 5,965,701, by D-Nle is meant D-norleucine, and D-Hle
represents D-homoleucine, D-Har represents D-homoarginine, and
D-nArg represents D-norarginine, which is one carbon shorter than
D-Arg. By D-Nal is meant the D-isomer of alanine that is
substituted by naphthyl on the 3-carbon. Preferably, D-2Nal is
employed, ie the attachment to naphthalene is at the 2-position on
the ring structure; however, D-1Nal may also be used. The
abbreviations D-Cpa and D-Fpa are used to represent, respectively,
chloro D-Phe and fluoro-D-Phe, With D-4Cpa, D-2Fpa, D-3Fpa and
D-4Fpa being preferred. D-Npa means nitro-D-Phe, and D-Mpa is used
to represent methyl D-Phe. D-3.4Cpa means 3,4-dichloro-D-Phe. D-Acp
represents D-Ala(cyclopentyl). D-Orn represents D-ornithine, and
D-Dbu represents alpha, gamma-diamino butyric acid. CML represents
C.sup..alpha.methyl Len, and CMP and CMO represent C.sup..alpha.Me
Phe and C.sup..alpha.Me Orn. By D-4Amf is meant D-4(NH2CH2)Phe, and
by D-Gmf is meant Amf(amidino) Which represents D-Phe Where the
4-position is substituted With CH2NHC(NH)NH2. Amd represents
amidino, and the symbol D-Amf(Amd) is also used. By D-Tic is meant
D-1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid. In Ala(Thi),
Thi represents the thienyl group, Which is preferably linked at its
2-position to alanine, although 3-thienyl is an equivalent. By Ily
and Ior are respectively meant isopropyl Lys and isopropyl Orn
where the side chain amino group is alkylated with isopropy.
[0059] (dd) One or more compounds as disclosed in U.S. Pat. No.
7,713,937, synthetic peptide amides that exhibit strong kappa
agonist activity and low penetration into the brain (e.g.: they are
peripherally restricted), having the formula:
##STR00027##
[0060] and stereoisomers, mixture of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, solvates, acid salt
hydrates, N-oxides and isomorphic crystalline forms thereof,
wherein each Xaa1 is independently chosen from
(A)(A')D-phenylalanine, (A)(A')(.alpha.-Me)D-phenylalanine,
D-tyrosine, D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid,
D-phenylglycine, D-neopentylglycine, D-homophenylalanine,
.beta.-(E)D-Ala and D-tert-butyl-Gly, wherein (A) and (A') are each
phenyl ring substituents independently chosen from --H, --F, --Cl,
--NO2, --CH3, --CF3, --CN, --CONH2, and wherein each (E) is
independently chosen from tert-butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and
benzothienyl. Each Xaa2 is independently chosen from
(A)(A')D-phenylalanine. (A)(A')(.alpha.-Me)D-phenyl-alanine,
naphthyl-1-D-alanine, naphthyl-2-D-alanine, D-tyrosine,
(E)D-alanine, and D-tryptophan. Each Xaa3 is independently chosen
from D-norleucine, D-phenylalanine, (E)D-alanine, D-leucine,
(.alpha.-Me)D-leucine, D-homoleucine, D-valine, and D-methionine.
Each Xaa4 is independently chosen from (B)2D-arginine,
(B)2D-norarginine, (B)2D-homoarginine, .zeta.-(B)D-homolysine,
D-2,3-diaminopropionic acid, .epsilon.-(B)D-lysine,
.epsilon.-(B)2-D-lysine, D-(NH2CH2)phenylalanine,
amidino-D-(NH2CH2-)phenylalanine, .gamma.-(B)2D-diamino butyric
acid, .delta.-(B)2.alpha.-(B')D-ornithine,
D-2-amino-3(4-piperidyl)propionic acid,
D-2-amino-3(2-aminopyrrolidyl)propionic acid,
D-.alpha.-amino-.beta.-amidino-propionic acid,
.alpha.-amino-4-piperidineacetic acid,
cis-.alpha.,4-diaminocyclohexane acetic acid,
trans-.alpha.,4-diaminocyclohexaneacetic acid,
cis-.alpha.-amino-4-methyl-aminocyclo-hexane acetic acid,
trans-.alpha.-amino-4-methylaminocyclohexane acetic acid,
.alpha.-amino-1-amidino-4-piperidineacetic acid,
cis-.alpha.-amino-4-guanidino-cyclohexane acetic acid, and
trans-.alpha.-amino-4-guanidinocyclohexane acetic acid, wherein
each (B) is independently chosen from --H and C1-C4 alkyl, and (B')
is H or (.alpha.-Me); and p is zero or 1.
[0061] In another embodiment G is selected from one of the
following three moieties: (i) G is
##STR00028##
[0062] wherein p, q, r, s and t are each independently zero or 1,
provided that at least one of s and t are 1; and L is a linker
chosen from .epsilon.-D-lysine, .epsilon.-lysine,
.delta.-D-ornithine, .epsilon.-ornithine, .gamma.-amino-butyric
acid, 8-aminooctanoic acid, 11-amino-undecanoic acid,
8-amino-3,6-dioxa-octanoic acid, 4-amino-4-carboxylic piperidine
and bis(D-Lys-Gly)Lactam. The synthetic peptide amides of this
embodiment are also herein interchangeably referred to as `dimers,`
`dimeric structures` or `synthetic peptide amide dimers` since they
include two synthetic peptide amide components joined by the
linking moiety, L.
[0063] (ii) G is
##STR00029##
[0064] and p is I; and the moiety
##STR00030##
[0065] is an optionally substituted 4 to 8-membered heterocyclic
ring moiety wherein Y is C or N and Z is a carbon atom, a nitrogen
atom, an oxygen atom, a sulfur atom, a sulfoxide group, or a
sulfonyl group; provided that when such ring moiety is a 6-, 7- or
8-membered ring, Y and Z are separated by at least two ring atoms;
and provided further that when such ring moiety is aromatic, then Y
is a carbon atom; and
[0066] (iii) G is
##STR00031##
[0067] wherein J is a 5-, 6-, or 7-membered heterocyclic ring
moiety comprising 1, 2, or 3 heteroatoms in the ring, wherein R3
and R4 are each independently selected from H, C1-C3 alkyl, halo,
--OH, --CF3, --NH2, --COOH and amidino; and R5 and R6 are each
independently chosen from H, C1-C3 alkyl, oxo, halo, --OH, --CF3,
--NH2, --COOH and amidino; wherein W' is chosen from: the moiety
--NH--(CH2)b- with b equal to zero, 1, 2, 3, 4, 5, or 6; and the
moiety --NH--(CH2)c-O-- with c equal to 2 or 3.
[0068] In another embodiment, V is C1-C6 alkyl, and e is zero or 1,
wherein when e is zero, then V is null and, R1 and R2 are directly
bonded to the same or different ring atoms; wherein
[0069] (a) R1 is --H, --OH, halo, CF3, --NH2, --COOH, C1-C6 alkyl,
C1-C6 alkoxy, amidino, C1-C6 alkyl-substituted amidino, aryl,
optionally substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val,
Leu, Ile, Lys, Arg, Orn, Ser, Thr, CN, CONH2, COR', SO2R',
CONR'R'', NHCOR', OR', or SO2NR'R''; wherein said optionally
substituted heterocyclyl is optionally singly or doubly substituted
with substituents independently selected from the group consisting
of C1-C6 alkyl, --C1-C6 alkoxy, oxo, --OH, --Cl, --F, --NH2, --NO2,
--CN, --COOH, and amidino; wherein R' and R'' are each
independently --H, C1-C8 alkyl, aryl, or heterocyclyl or R' and R''
are combined to form a 4-, 5-, 6-, 7-, or 8-membered ring, which
ring is optionally substituted singly or doubly with substituents
independently selected from the group consisting of C1-C6 alkyl,
--C1-C6 alkoxy, --OH, --Cl, --F, --NH2, --NO2, --CN, and --COOH,
amidino; and R2 is H, amidino, singly or doubly C1-C6
alkyl-substituted amidino, --CN, --CONH2, --CONR'R'', --NHCOR',
--SO2NR'R'', or --COOH; or
[0070] (b) R1 and R2 taken together can form an optionally
substituted 4-, 5-, 6-, 7-, 8- or 9-membered heterocyclic
monocyclic or bicyclic ring moiety which is bonded to a single ring
atom of the Y and Z-containing ring moiety; or
[0071] (c) R1 and R2 taken together with a single ring atom of the
Y and Z-containing ring moiety can form an optionally substituted
4-, 5-, 6-, 7-, or 8-membered heterocyclic ring moiety to form a
spiro structure; or
[0072] (d) R1 and R2 taken together with two or more adjacent ring
atoms of the Y and Z-containing ring moiety can form an optionally
substituted 4-, 5-, 6-, 7-, 8- or 9-membered heterocyclic
monocyclic or bicyclic ring moiety fused to the Y and Z-containing
ring moiety; and wherein each of said optionally substituted 4-,
5-, 6-, 7-, 8- or 9-membered heterocyclic ring moieties comprising
R1 and R2 is optionally singly or doubly substituted with
substituents independently selected from the group consisting of
C1-C6 alkyl, --C1-C6 alkoxy, optionally substituted phenyl, oxo,
--OH, --Cl, --F, --NH2, --NO2, --CN, --COOH, and amidino; provided
that when the Y and Z-containing ring moiety is a six or
seven-membered ring having a single ring heteroatom and such
heteroatom is N, and e is zero, then R1 is not --OH, and R1 and R2
are not both --H; provided further that when the Y and Z-containing
ring moiety is a non-aromatic six membered ring comprising two ring
heteroatoms, both Y and Z are N, W is null, and -Ve(R1)(R2) is
attached to Z, then Ve(R1)(R2) is selected from the group
consisting of amidino, C1-C6 alkyl-substituted amidino,
dihydroimidazole, --CH2COOH and --CH2C(O)NH2; and lastly, provided
that if the Y and Z-containing ring moiety is a six membered ring
comprising an S or O ring heteroatom, or if the Y and Z-containing
ring moiety is a six membered ring comprising two ring heteroatoms,
wherein both Y and Z are N and W is null, or if the Y and
Z-containing ring moiety is a six membered aromatic ring comprising
a single ring heteroatom, which heteroatom is N, then, when e is
zero, R1 and R2 are not both --H.
[0073] In one embodiment the synthetic peptide amides of
formula:
##STR00032##
[0074] and stereoisomers, mixtures of stereoisomers, racemates,
prodrugs, pharmaceutically acceptable salts, hydrates, solvates,
acid salt hydrates, N-oxides and isomorphic crystalline forms
thereof; wherein Xaa1 is chosen from (A)(A')D-Phe,
(.alpha.-Me)D-Phe, D-Tyr, D-Tic, D-phenylglycine, D
homophenylalanine, .beta.-(E)D-Ala and D-tert-butyl-Gly, wherein
(A) and (A') are each phenyl ring substituents independently chosen
from --H, --F, --Cl, --NO2, --CH3, --CF3, --CN, and CONH2, and (E)
is chosen from tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and benzothienyl.
Xaa2 is chosen from (A)(A')D-Phe, (.alpha.-Me)D-Phe, D-1Nal,
D-2Nal, D-Tyr, (E)D-Ala and D-Trp; and Xaa3-Xaa4--is chosen from
fD-Nle-(B)2D-Arg-, D-Leu-.delta.-(B)2.alpha.-(B')D-Orn-, and
(.alpha.-Me)D-Leu-.delta.(B')2-.alpha.(B')D-Orn-; wherein each (B)
is independently chosen from --H and C1-C4 alkyl, and (B') is --H
or (.alpha.-Me). W in the above formula is chosen from one of the
following three options:
[0075] (i) Null, provided that when W is null, Y is N; or
[0076] (ii) --N--(CH2)b with b equal to zero, 1, 2, 3, 4, 5, or 6;
or
[0077] (iii) --N--(CH2)n-O-- with c equal to 2, or 3, provided that
Y is a carbon atom.
[0078] In one embodiment the Y- and Z-containing moiety in the
above formula is an optionally substituted 4-8 membered saturated
mono- or dinitrogen heterocyclic ring moiety, in which no ring atom
other than Y and Z is a heteroatom, Y is C or N, Z is C or N, and
at least one of Y and Z is N, and provided that in the case of a 4
or 5 membered heterocyclic ring, either Y or Z is C, and in the
case of a dinitrogen heterocycle, Y and Z are separated by two or
more ring carbon atoms.
[0079] In another embodiment, when the Y- and Z-containing ring
moiety is a saturated six-membered ring that includes only two ring
heteroatoms which are both N and W is null, then Z is not N.
[0080] In another embodiment the moiety V is C1-C6 alkyl, and e is
zero or 1, wherein when e is zero, then V is null and, R1 and R2
are directly bonded to the same or different ring atoms. R1 is H,
OH, --NH2, --COOH, C1-C6 alkyl, C1-C6 alkoxy, amidino, C1-C6
alkyl-substituted amidino, dihydroimidazole, Pro-amide, Pro, Gly,
Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, CN, CONH2, CONR'R'',
NHCOR', or SO2NR'R'', wherein R' and R'' are each independently H,
or C1-C8 alkyl, or R' and R'' are combined to form a 4-, 5-, 6-,
7-, or 8-membered ring which ring is optionally substituted singly
or doubly with substituents independently chosen from C1-C6 alkyl,
--OH, --Cl, --F, --NH2, --NO2, --CN, and --COOH, amidino; and R1 is
H, amidino, singly or doubly C1-C6 alkyl-substituted amidino, --CN,
--CONH2, CONR'R'', --NHCOR', --SO2NR'R''. or --COOH.
[0081] In one embodiment, formula I is subject to two provisos: (i)
when the Y and Z-containing ring moiety is a six or seven membered
ring and when one of Y and Z is C and e is zero, then R1 is not OH,
and R1 and R2 are not both H; and (ii) when the Y and Z-containing
ring moiety is a six membered ring, both Y and Z are N and W is
null, then -(V)eR1R2 is attached to a ring atom other than Z; and
if e is zero, then R1 and R2 are not both --H.
[0082] In certain embodiments the synthetic peptide amides have the
formula:
##STR00033##
wherein Xaa1 is chosen from (A)(A')D-Phe, (.alpha.-Me)D-Phe, D-Tyr,
D-Tic, (E)D-Ala and D-tert-butyl-Gly, wherein (A) and (A') are each
phenyl ring substituents independently chosen from --H, --F, --Cl,
NO2, --CH3, --CF3, --CN, --CON--H2, and wherein (E) is selected
from the group consisting of tert-butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and
benzothienyl. Xaa2 is chosen from (A)(A')D-Phe, (.alpha.-Me)D-Phe,
D-1Nal, D-2Nal, D-Tyr, (E)D-Ala and D-Trp. Xaa3 is chosen from
D-Nle, D-Phe, cyclopentyl-D-Ala, D-Leu, (.alpha.-Me)D-Leu, D-Hle,
D-Val, and D-Met. Xaa4 is chosen from (B)2D-Arg, (B)2D-nArg
(B)2D-Har, .zeta.-(B)D-Hlys, D-Dap, .epsilon.-(B)D-Lys,
.epsilon.-(B)2-D-Lys, D-Amf, amidino-D-Amf, .gamma.-(B)2D-Dbu,
.delta.-(B)2.alpha.-(B')D-Orn, D-2-amino-3(4-piperidyl)propionic
acid, D-2-amino-3(2-aminopyrrolidyl)propionic acid.
D-.alpha.-amino-.beta.-amidinopropionic acid,
(R)-.alpha.-amino-4-piperidineacetic acid,
cis-.alpha.,4-diaminocyclohexane acetic acid,
trans-.alpha.,4-diaminocyclohexaneacetic acid,
cis-.alpha.-amino-4-methylamino-cyclohexane acetic acid,
trans-.alpha.-amino-4-methylamino-cyclohexane acetic acid,
.alpha.-amino-1-amidino-4-piperidineacetic acid,
cis-.alpha.-amino-4-guanidinocyclohexane acetic acid, and
trans-.alpha.-amino-4-guanidinocyclohexane acetic acid, wherein
each (B) is independently selected from the group consisting of H
and C1-C4 alkyl, and (B') is H or (.alpha.-Me). The moiety W is
chosen from one of the following three options: (i) null; (ii)
--N--(CH2)b with b equal to zero, 1, 2, 3, 4, 5, or 6; and (iii)
--N--(CH2)c-O-- with c equal to 2 or 3 provided Y is a carbon
atom.
[0083] In this embodiment, the Y- and Z-containing ring moiety,
##STR00034##
is an optionally substituted 6-8 membered saturated heterocyclic
ring moiety, wherein no ring atom other than Y and Z is a
heteroatom. Y and Z are separated by at least two carbon ring
atoms. Y is C or N, and Z is S, O or N.
[0084] The moiety V is C1-C6 alkyl, and e is zero or 1, wherein
when e is zero, then V is null and, R1 and R2 are directly bonded
to the same or different ring atoms; R1 is H, OH, --NH2, --COOH,
C1-C6 alkyl, amidino, C1-C6 alkyl-substituted amidino,
dihydroimidazole, D-Pro, Gly, D-Ala, D-Val, D-Leu, D-Ile, D-Lys,
D-Arg, D-Orn, D-Ser, D-Thr, --CN, --CONH2, --CONR'R'', NHCOR', or
--SO2NR'R'', wherein R' and R'' are each independently H, or C1-C8
alkyl, or R' and R'' are combined to form a 4-, 5-, 6-, 7-, or
8-membered ring which ring is optionally substituted singly or
doubly with substituents independently chosen from C1-C8 alkyl,
--OH, --Cl, --F, --NH2, --NO2, --CN, and --COOH, amidino; and R2 is
--H, amidino, C1-C6 alkyl-substituted amidino, --CN, --CONH2,
--CONR'R'', NHCOR', SO2NR'R'', or --COOH.
[0085] In certain embodiments one of the following three provisos
apply: when e is zero, then R1 and R2 are not both H; when W is
--N--(CH2)c-O--, then Y is C and c is 2 or 3; or (iii) if Z is N,
then Y is N, W is null, the Y and Z-containing ring moiety is a non
aromatic six membered ring, and -Ve(R1)(R2) is attached to Z, and
-Ve(R1)(R2) is chosen from amidino, C1-C6 alkyl-substituted
amidino, dihydroimidazole, --CH2COOH, and --CH2C(O)NH2.
[0086] In certain other embodiments the synthetic peptide amides
are dimers that include two synthetic peptide amide components
joined by a linking moiety, L. In one aspect the synthetic peptide
amides have the formula:
##STR00035##
[0087] In the above formula, each Xaa1 is independently chosen from
(A)(A')D-Phe, (.alpha.-Me)D-Phe, D-Tyr, D-Tic, (E)D-Ala and
D-tert-butyl-Gly, wherein (A) and (A') are each phenyl ring
substituents independently chosen from --H, --F, --Cl, --NO2,
--CH3, --CF3, --CN, --CONH2, and wherein (E) is chosen from
tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
furyl, pyridyl, thienyl, thiazolyl and benzothienyl. Each Xaa2 is
independently chosen from (A)(A')D-Phe, (.alpha.-Me)D-Phe, D-1Nal,
D-2Nal, D-Tyr, and D-Trp; and r is zero or I. Each Xaa3 is
independently chosen from D-Nle, D-Phe, cyclopentyl-D-Ala, D-Leu,
(.alpha.-Me)D-Leu, D-Hle, D-Val, and D-Met; and s is zero or 1.
Each Xaa4 is independently chosen from (B)2D-Arg. (B)2D-nArg,
(B)2D-Har. .epsilon.-(B)D-Hlys, D-2,3-diaminopropionic acid,
.epsilon.-(B)D-Lys, .epsilon.-(B)-2-D-Lys, D-Amf, amidino-D-Amf,
(B)2D-Dbu, .delta.-(B)2.alpha.-(B')D-Orn,
D-2-amino-3(4-piperidyl)propionic acid,
D-2-amino-3(2-aminopyrrolidyl)propionic acid,
D-.alpha.-amino-.beta.-amidinopropionic acid, wherein each (B) is
independently selected from the group consisting of H and C1-C4
alkyl, and (B') is H or (.alpha.-Me); and p, q, r, s and t are each
independently zero or 1, provided that at least one of q, r, s and
t are 1. In certain aspects of the invention, at least one of s and
t is 1.
[0088] The moiety L is a linker chosen from .epsilon.-D-Lys,
.epsilon.-Lys, .delta.-D-Orn, .delta.-Orn, .gamma.-aminobutyric
acid, 8-aminooctanoic acid, 11-aminoundecanoic acid,
8-amino-3,6-dioxaoctanoic acid, amidino-4-amino-4-carboxylic
piperidine and bis(D-Lys-Gly)Lactam.
[0089] Stereoisomers, mixtures of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, solvates, acid salt
hydrates, N-oxides and isomorphic crystalline forms of these
synthetic peptide amides are also contemplated within the scope of
the present invention.
[0090] In another embodiment, the synthetic peptide amide has the
formula:
##STR00036##
wherein G is
##STR00037##
and q is 0 or 1; r is 0 or 1; s is 0 or 1; p and t are each
independently 0 or 1, provided that at least one of q, r, s and t
are 1; and L is a linker chosen from .epsilon.-D-Lys,
.epsilon.-Lys, .delta.-D-Orn, .delta.-Orn, .gamma.-aminobutyric
acid, 8-amino-octanoic acid, 11-amino-undecanoic acid,
8-amino-3,6-dioxaoctanoic acid, 4-amino-4-carboxylic piperidine and
bis(D-Lys-Gly)Lactam.
[0091] In another embodiment, the synthetic peptide amides have the
formula:
##STR00038##
wherein G is
##STR00039##
and J is a 5-, 6-, or 7-membered heterocyclic ring moiety having 1,
2, or 3 heteroatoms in the ring, wherein R3 and R4 are each
independently chosen from --H, C1-C3 alkyl, halo, --OH, --CF3,
--NH2, --COOH and amidino; and R5 and R6 are each independently
chosen from --H, C1-C3 alkyl, oxo, halo, --OH, --CF3, --NH2, --COOH
and amidino.
[0092] In another embodiment, the synthetic peptide amide has the
formula:
##STR00040##
wherein G is
##STR00041##
and W is null, Y is N and Z is C. In one aspect, the Y and
Z-containing ring moiety is a six-membered saturated ring
comprising a single ring heteroatom.
[0093] In another embodiment, G is
##STR00042##
and Y and Z are both N and are the only ring heteroatoms in the Y
and Z-containing ring moiety. In another embodiment, e is zero, and
substituents R1 and R2 taken together with zero, one or two ring
atoms of the Y and Z-containing ring moiety comprise a monocyclic
or bicyclic 4-9 membered heterocyclic ring moiety. In one aspect of
this embodiment, R1 and R2 taken together with one ring atom of the
Y and Z-containing ring moiety comprise a 4-, 5-, 6-, 7-, or
8-membered heterocyclic ring moiety which with the Y and
Z-containing ring moiety forms a spiro structure and W is null.
[0094] In another embodiment, G is
##STR00043##
and e is zero and R1 and R2 are bonded directly to the same ring,
atom. Alternatively, in another embodiment, R1 is H, OH, --NH2,
--COOH, --CH2COOH, C1-C3 alkyl, amidino, C1-C3 alkyl-substituted
amidino, dihydroimidazole, D-Pro, D-Pro amide, or CONH2 and wherein
R2 is H, --COOH, or C1-C3 alkyl.
[0095] In another embodiment, G is chosen from the following
groups:
##STR00044## ##STR00045## ##STR00046##
[0096] In one embodiment, each Xaa1 is D-Phe, each Xaa2 is D-Phe,
each Xaa3 is D-Leu and each Xaa4 is D-Lys. In another embodiment,
each Xaa1 is D-Ala(2-thienyl), each Xaa2 is D-Phe, each Xaa3 is
D-Nle, and each Xaa4 is D-Arg.
[0097] In another embodiment, G is
##STR00047##
and the dipeptide Xaa3-Xaa4 is chosen from D-Leu-D-Orn and
D-Nle-D-Arg. In another embodiment Xaa1Xaa2 is D-Phe-D-Phe. In
another embodiment Xaa1 is D-(4-F)Phe, and Xaa2 is D-(4-Cl)Phe.
[0098] In another embodiment each Xaa1 is D-Phe or D-Ala(2-thienyl)
and each Xaa2 is D-(4-Cl)Phe. In another embodiment, each Xaa3 is
D-Leu or D-Nle.
[0099] In another embodiment G is
##STR00048##
and Xaa1 is chosen from D-Phe, D-(4-F)Phe, D-(2-F)Phe, cyclopentyl
D-Ala, 2-thienyl D-Ala, Xaa2 is chosen from D-Phe, D-(4-F)Phe,
D-(4-Cl)Phe, D-1Nal, D-2Nal, and D-Trp, and Xaa3-Xaa4 is chosen
from D-Nle-D-Arg, D-Leu-D-Lys and D-Leu-D-Orn.
[0100] In one embodiment Xaa1 is (A)(A')D-Phe, and in one aspect,
each Xaa1 is D-Phe. In another embodiment each Xaa2 is D-Phe. In
another embodiment, each Xaa3 is chosen from D-Nle, and D-Leu. In
another embodiment each Xaa4 is chosen from .delta.(B)2D-Orn, D-Lys
and D-Arg. In one aspect, each Xaa4 is .delta.(B)2D-Orn and each
(B) chosen from --H, methyl and isopropyl. In another aspect each
Xaa4 is (B)2D-Orn, wherein one (B) is H, and the other (B) selected
from the group consisting of methyl and isopropyl. In another
particular aspect each Xaa4 is D-Orn.
[0101] In another embodiment each Xaa4 is chosen from
.epsilon.(B)2D-Lys, (B)2D-Arg, and .delta.-(B)2D-Orn. In another
particular aspect each Xaa4 is chosen from D-Arg, (Et)2D-Arg, and
.delta.-(B)D-Orn, and (B) is H, Me, iPr, or Bu.
[0102] In another embodiment G is
##STR00049##
and W is null.
[0103] In another embodiment G is
##STR00050##
and W is --N--(CH2)b with b equal to 0, 1, 2, 3, or 4. In one
aspect b is zero and Y is a carbon atom. In another aspect b is 1
or 2 and Y is a nitrogen atom. In another embodiment W is
--N--(CH2)c-O--. In one particular aspect c is 1 or 2. In another
aspect the Y and Z-containing ring moiety is a four or five
membered ring and Y is a nitrogen atom. In another embodiment the Y
and Z-containing ring moiety is a four or five membered ring and Y
is a carbon atom.
[0104] In another embodiment the Y and Z-containing ring moiety is
a six or seven membered ring, Y is nitrogen and Z is a carbon atom.
In another alternative, the Y and Z-containing ring moiety is a six
membered ring. In one aspect the Y and Z-containing ring moiety is
a seven membered ring. In still another aspect the Y and
Z-containing ring moiety is a six or seven membered ring and both Y
and Z are nitrogen atoms.
[0105] In another embodiment e is zero and R1 and R2 are bonded
directly to the same ring atom. In one aspect e is zero, R2 is --H
and R1 is bonded directly to a carbon ring atom adjacent to Z. In
another aspect R1 is H, amidino, C1-C3 alkyl substituted amidino,
C1-C3 alkyl, dihydroimidazole, D-Pro, D-Pro amide, or --CONH2 and
wherein e is zero and R2 is --H. In another aspect R1 is --H,
amidino, or methyl amidino. In one aspect the Y and Z-containing
ring moiety is a five membered ring, e is zero and R1 is
--COOH.
[0106] In another embodiment G is
##STR00051##
and Xaa1 is D-Phe, Xaa2 is D-Phe, Xaa3 is D-Leu, Xaa4 is
.epsilon.(B)2D-Lys, or .delta.-(B)2D-Orn, wherein (B) is --H,
methyl, or isopropyl; further wherein W is null, the Y and
Z-containing ring moiety is a six or seven membered ring. Y is a
nitrogen atom, e is zero, R1 is --NH2, amidino, C1-C3 alkyl, C1-C3
alkyl-substituted amidino, dihydroimidazole, D-Pro, or D-Pro amide,
and R2 is H or --COOH.
[0107] In certain embodiments, there are two independent
occurrences of the residues Xaa1, Xaa2, Xaa3 and Xaa4. For
instance, in embodiments having the formula:
##STR00052##
wherein G is:
##STR00053##
and one or more of q, r, and s is 1 or both p and t are 1, then
there are two occurrences of Xaa1, Xaa2, Xaa3 and Xaa4
respectively. In such embodiments, each instance of each of the
residues Xaa1, Xaa2, Xaa3 and Xaa4 can be identical.
[0108] Alternatively, and in other embodiments, each instance of
one or more of the pairs of residues Xaa1, Xaa2, Xaa3 or Xaa4 can
be different. For example, one instance of Xaa1 can be
D-phenylalanine, while the second instance of Xaa1 in the same
molecule can be a different Xaa1 residue, such as
D-(4-F)phenylalanine. Similarly, one instance of Xaa2 can be
D-phenylalanine, while the second instance of Xaa2 in the same
molecule can be D-Ala(2-thienyl). Likewise, one instance of Xaa3
can be D-norleucine, while the second instance of Xaa3 in the same
molecule can be D-leucine. In the same manner, one instance of Xaa4
can be D-ornithine, while the second instance of Xaa4 in the same
molecule can be D-arginine, and so on.
[0109] In one embodiment, Xaa1 is D-Ala(2-thienyl). In another
embodiment Xaa1 is D-(4-F)phenylalanine and Xaa2 is
D-(4-Cl)phenylalanine. In another embodiment each Xaa1 is
D-phenylalanine or D-Ala(2-thienyl) and each Xaa2 is
D-(4-Cl)phenylalanine.
[0110] In another embodiment Xaa1-Xaa2 is
D-phenylalanine-D-phenylalanine.
[0111] In one embodiment each Xaa3 is chosen from D-norleucine and
D-leucine. In another embodiment each Xaa2 is D-phenylalanine, each
Xaa3 is D-norleucine and each Xaa4 is D-arginine. In another
embodiment each Xaa3 can be D-leucine or D-norleucine.
[0112] In another embodiment Xaa4 is chosen from
.delta.(B)2D-ornithine and D-arginine. Alternatively, each Xaa4 is
.delta.(B)2D-ornithine and each (B) is chosen from --H, methyl and
isopropyl. In still another embodiment, each Xaa4 is
(B)2D-ornithine, wherein one (B) is --H, and the other (B) chosen
from methyl and isopropyl. In one aspect, each Xaa4 is
(B)2D-arginine, or .delta.-(B)2D-ornithine. In another embodiment
each Xaa4 can be a residue chosen from D-arginine, (Et)2D-arginine,
and .delta.-(B)D-ornithine, and wherein (B) is --H, methyl,
isopropyl, or butyl. In one embodiment the dipeptide Xaa3-Xaa4 is
chosen from D-leucine-D-ornithine and D-norleucine-D-arginine.
[0113] In one particular embodiment the synthetic peptide amide has
the formula
##STR00054##
wherein G is:
##STR00055##
and b is zero and Y is a carbon atom. In another embodiment, b is 1
or 2 and Y is a nitrogen atom. In a particular aspect of the
invention, b is 2.
[0114] In another embodiment G is
##STR00056##
and the Y- and Z-containing moiety is
[.omega.(4-aminopiperidine-4-carboxylic acid)]-OH. In one
particular embodiment Xaa1 is chosen from D-Phe, D-(4-F)Phe,
D-(2-F)Phe, cyclopentyl D-Ala, 2-thienyl D-Ala, Xaa2 is chosen from
D-(4-F)Phe, D-(4-Cl)Phe, D-1Nal, D-2Nal, and D-Trp, and Xaa3-Xaa4
is chosen from D-Nle-D-Arg and D-Leu-D-Orn.
[0115] In another embodiment W is an N-alkoxyl linker of the
formula: --N--(CH2)2-O--. In an alternative embodiment W is null
and Xaa1Xaa2Xaa3Xaa4 is directly bonded to Y. In a second
alternative embodiment. W is --NH--(CH2)2-.
[0116] In another particular embodiment, the Y and Z-containing
ring moiety is a four or five membered ring and Y is a nitrogen
atom. Alternatively, the Y-and Z-containing ring moiety can be a
four or five membered ring wherein Y is a carbon atom. In a
different embodiment, the Y and Z-containing ring moiety is a 6- or
7-membered ring, Y is a nitrogen atom and Z is a carbon atom. In
one aspect of this embodiment, the Y and Z-containing ring moiety
is a 6-membered ring. Alternatively, the Y and Z-containing ring
moiety can be a seven membered ring. In one aspect of this
embodiment, the Y and Z-containing ring moiety is a 6- or
7-membered ring and both Y and Z are nitrogen atoms.
[0117] In another particular embodiment the Y- and Z-containing
ring moiety is a six or seven membered ring, or an eight-membered
ring, Y is a carbon atom, and Z is a nitrogen atom. In one aspect,
Y is a nitrogen atom and Z is a carbon atom. In an alternative
embodiment Y and Z are each nitrogen atoms.
[0118] In another particular embodiment the Y- and Z-containing
ring moiety is an optionally substituted 4-, 5-, 6-, 7-, or
8-membered heterocyclic ring moiety wherein Y is a carbon or a
nitrogen atom and Z is carbon, nitrogen, oxygen, sulfur, sulfoxide,
or sulfonyl; and the 4-, 5-, 6-, 7-, or 8-membered heterocyclic
ring moiety is optionally singly or doubly substituted with
substituents independently chosen from C1-C6 alkyl, --C1-C6 alkoxy,
oxo, --OH, --Cl, --F, --NH2, --NO2, --CN, --COOH, and amidino. In
one aspect when the Y- and Z-containing ring moiety is a six, seven
or eight-membered ring, then Y and Z are separated by at least two
ring atoms. In another aspect, when the Y- and Z-containing ring
moiety is non-aromatic and Z is a carbon or a nitrogen atom, then
such ring moiety includes at least one sulfur or oxygen ring
heteroatom. In a particular aspect, when the Y- and Z-containing
ring moiety is aromatic, then Y is a carbon atom.
[0119] In one embodiment, R1 is --H, --OH, --NH2, --COOH, C1-C3
alkyl, amidino, C1-C3 alkyl-substituted amidino, dihydroimidazole,
D-Pro, D-Pro amide, or --CONH2. In another particular embodiment R2
is --H, --COOH, or C1-C3 alkyl. In one aspect, only one of R1 and
R2 is a hydrogen atom. In a particular embodiment R1 is --H, D-Pro,
D-Pro amide, or --NH2 and R2 is H or --COOH. In one aspect of this
embodiment, R1 is --NH2 and 2 is --COOH.
[0120] In one embodiment, the operator, e is zero and R1 and R2 are
bonded directly to the same ring atom. In a particular embodiment,
e is zero. R2 is --H and R1 is bonded directly to a carbon ring
atom adjacent to Z. In another particular embodiment R1 is --H,
amidino, C1-C3 alkyl substituted amidino, C1-C3 alkyl,
dihydroimidazole, D-Pro, D-Pro amide, or --CONH2 and e is zero and
R2 is --H.
[0121] In one embodiment, Xaa1 is D-Phe, Xaa2 is D-Phe, Xaa3 is
D-Leu, Xaa4 is .delta.-(B)2D-Orn, wherein (B) is --H, methyl, or
isopropyl; such that wherein W is null, the Y and Z-containing ring
moiety is a six or seven membered ring, Y is a nitrogen atom, e is
zero. R1 is --NH2, amidino, C1-C3 alkyl, C1-C3 alkyl-substituted
amidino, dihydroimidazole, D-Pro, or D-Pro amide, and R2 is H or
--COOH.
[0122] In one embodiment, Xaa1 is chosen from (A) D-Phe,
(.alpha.-Me)D-Phe, D-Tyr, D-Tic, (tert-butyl)D-Gly, and
.beta.-(E)D-Ala, wherein (A) is chosen from --H, --F, --Cl, --NO2,
and --CH3, and (E) is chosen from tert-butyl, cyclopentyl and
thienyl; Xaa2 is chosen from (A)(A')D-Phe, D-1Nal, D-2Nal, D-Tyr,
and D-Trp, wherein (A') is H or Cl; Xaa3 is chosen from D-Nle,
D-Phe, (cyclopentyl) D-Ala, D-Leu, (.alpha.-Me)D-Leu, D-Hle, D-Val,
and D-Met; and Xaa4 is chosen from D-Arg, (ethyl)2D-Arg, D-Nar,
D-Har, (ethyl)2D-Har, F-(isopropyl)D-Lys, D-Lys, D-Amf,
amidino-D-Amf, .beta.-amidino-D-Dap, D-Dbu, D-Orn,
.alpha.-(methyl)D-Orn and .delta.-(isopropyl)D-Orn.
[0123] In another embodiment, Xaa1 Xaa2 is D-Phe-D-Phe, Xaa3 is
D-Leu or D-Nle and Xaa4 is chosen from (B)2D-Arg, D-Lys, (B)2D-Nar,
(B)2D-Har, .delta.-(B)D-Hlys, D-Dap, amidino-D-Dap,
.epsilon.-(B)D-Lys, .epsilon.-(B)2-D-Lys, D-Amf, amidino-D-Amf,
.gamma.-(B)2D-Dbu and .delta.-(B)2.alpha.-(B')D-Orn.
[0124] In another embodiment, Xaa4 is chosen from D)-Lys,
(B)2D-Har, .epsilon.(B)-D-Lys, .delta.(B)2-.alpha.(B')D-Orn and
.epsilon.(B)2-D-Lys.
[0125] In another embodiment, G is
##STR00057##
[0126] In another embodiment, the integers p, q, r, s and t are
each 1.
[0127] In another embodiment, Xaa1 is chosen from (A) D-Phe,
(.alpha.-Me)D-Phe, D-Tyr, D-Tic, (tert-butyl)D-Gly, and
.beta.-(E)D-Ala, wherein A is selected from the group consisting of
--H, --F, --Cl, --NO2, and --CH3, and (E) is selected from the
group consisting of tert-butyl, cyclopentyl and thienyl; Xaa2 is
selected from the group consisting of (A)(A')D-Phe, D-1Nal, D-2Nal,
D-Tyr, and D-Trp, wherein (A') is H or Cl; Xaa3 is selected from
the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu,
(.alpha.-Me)D-Leu, D-Hle, D-Val, and D-Met; and Xaa4 is selected
from the group consisting of D-Arg, (ethyl)2D-Arg, D-Nar, D-Har,
(ethyl)2D-Har, .epsilon.-(isopropyl)D-Lys, D-Lys, D-Amf,
amidino-D-Amf .beta.-amidino-D-Dap, D-Dbu, D-Om,
.alpha.-(methyl)D-Orn and .delta.-(isopropyl)D-Orn.
[0128] In another embodiment of the synthetic peptide amide of the
invention: Xaa1 is D-Phe; Xaa2 is D-Phe; Xaa3 is D-Leu and Xaa4 is
chosen from D-Nar, D-Orn, and (isopropyl)D-Orn.
[0129] In another embodiment, L is a linker chosen from
.epsilon.-D-Lys, .epsilon.-Lys, .delta.-D-Orn, .delta.-Orn,
4-amino-4-carboxylic piperidine and bis(D-Lys-Gly)Lactam.
[0130] In another embodiment, G is
##STR00058##
[0131] In another embodiment of the synthetic peptide amide, J is a
five-membered heterocyclic ring moiety. In an alternative
embodiment, J is a five-membered heterocyclic ring moiety that
includes two heteroatoms, which two heteroatoms are both N.
[0132] In another embodiment of the synthetic peptide amide, G
is
##STR00059##
[0133] In a particular aspect of this embodiment, W is null, and Y
is nitrogen. In another particular aspect of this embodiment, the Y
and Z-containing ring moiety is a five-membered saturated ring.
[0134] In another embodiment of the synthetic peptide amide, G is
an optionally substituted proline radical.
[0135] In another embodiment of the synthetic peptide amide, the Y
and Z-containing ring moiety is a six-membered saturated ring. In a
particular aspect of this embodiment, the Y and Z-containing ring
moiety comprises a single heteroatom and e is zero, and R1 and R2
taken together or with one or two ring atoms of the Y and
Z-containing ring moiety comprise an optionally substituted
monocyclic or bicyclic 4-, 5,6-, 7,8- or 9-membered heterocyclic
ring moiety. In a particular aspect of this embodiment, R1 and R2
taken together with one ring atom of the Y and Z-containing ring
moiety comprises a five-membered heterocyclic ring moiety having
only heteroatoms chosen from N and O, which heterocyclic ring
moiety with the Y and Z-containing ring moiety forms a spiro
structure.
[0136] In another embodiment of the synthetic peptide amide, the Y
and Z-containing ring moiety includes two heteroatoms. In a
particular aspect of this embodiment, the two heteroatoms of the Y
and Z-containing ring moiety are both nitrogen. In another
particular aspect of this embodiment, the integer e is zero, R2 is
hydrogen and the Y- and Z-containing ring moiety is 3-substituted
with R1. In still another particular aspect of this embodiment, the
two heteroatoms of the Y- and Z-containing ring moiety are nitrogen
and oxygen. In one particular aspect the Y- and Z-containing ring
moiety is 3-substituted with R1, the integer e is zero and R2 is
hydrogen. In another particular aspect the two heteroatoms of the
Y- and Z-containing ring moiety are nitrogen and sulfur. In still
another particular aspect the Y- and Z-containing ring moiety is
3-substituted with R1, e is zero and R2 is H.
[0137] In another embodiment of the synthetic peptide amide, G
is
##STR00060##
[0138] W is null, and Y is nitrogen and the Y and Z-containing ring
moiety is a seven-membered saturated ring comprising two
heteroatoms. In a particular aspect of this embodiment, Y and Z are
both nitrogen atoms and the moiety VeR1R2 is bonded to Z. In an
alternative aspect of this embodiment, Y is nitrogen and the second
heteroatom of the Y and Z-containing ring moiety is chosen from S
and O. In another alternative aspect of this embodiment. W is
--NH2-(CH2)b- and b is zero, 1, 2, or 3. In a particular aspect the
Y- and Z-containing ring moiety is a five-membered saturated ring
such as for instance, an optionally substituted proline radical.
Alternatively, the Y- and Z-containing ring moiety can be a
six-membered saturated ring, wherein for example, Y can be carbon
and Z can be nitrogen; alternatively, Y and Z can both be nitrogen
atoms.
[0139] In another embodiment of the synthetic peptide amide, G is
chosen from substituted piperidinyl, piperidinyl forming a spiro
structure with an optionally substituted heterocycle, piperidinyl
fused with an optionally substituted heterocycle, substituted
piperazinyl, 4-sulfonamidyl piperazinyl, 3-substituted piperazinyl,
substituted homopiperazinyl, optionally substituted
homomorpholinyl, optionally substituted homothiomorpholinyl,
3-substituted morpholinyl, 3-substituted thiomorpholinyl, 4-4 dioxo
thiomorpholinyl, and optionally substituted proline, and W is null;
or
##STR00061##
[0140] G is
[0141] wherein the moiety
##STR00062##
is chosen from substituted pyrazinyl, substituted pyridinyl,
substituted piperazinyl, optionally substituted pyrimidinyl,
substituted "reverse" piperidinyl (i.e. not bonded to W through the
ring nitrogen), optionally substituted heterocyclic bicycle,
optionally substituted proline, optionally substituted thiazolyl,
optionally substituted dioxolanyl, and optionally substituted
tetrahydropyranyl and W is --NH2-(CH2)b- and b is zero, 1, 2, or
3.
[0142] In another embodiment of the synthetic peptide amide, G is
chosen from substituted piperidinyl, piperidinyl forming a spiro
structure with an optionally substituted heterocycle, and
piperidinyl fused with an optionally substituted heterocycle. In a
particular aspect of this embodiment, G is chosen from substituted
piperazinyl, 4-sulfonamidyl piperazinyl, 3-substituted piperazinyl,
and substituted homopiperazinyl. In another alternative aspect, G
is chosen from optionally substituted homomorpholinyl, optionally
substituted homothiomorpholinyl, 3-substituted morpholinyl,
3-substituted thiomorpholinyl, and 4-4 dioxothiomorpholinyl. In
still another alternative aspect, G is an optionally substituted
proline.
[0143] In another embodiment of the synthetic peptide amide, W is
--NH2(CH2)b-, b is zero, 1, 2, or 3 and the moiety
##STR00063##
is chosen from optionally substituted thiazolyl, optionally
substituted dioxolanyl, and optionally substituted
tetrahydropyranyl. Alternatively, W is --NH2-(CH2)b-, b is zero, 1,
2, or 3 and the moiety
##STR00064##
is chosen from substituted pyrazinyl, substituted pyridinyl,
optionally substituted pyrimidinyl, and optionally substituted
heterocyclic bicycle. In another alternative, W is --NH2-(CH2)b-, b
is zero, 1, 2, or 3 and the moiety
##STR00065##
is chosen from substituted piperazinyl and 4-substituted
piperidinyl.
[0144] In another embodiment of the synthetic peptide amide, W is
--NH2-(CH2)b-, b is zero, 1, 2, or 3 and the moiety
##STR00066##
is an optionally substituted proline moiety.
[0145] In another embodiment of the synthetic peptide amide, e is
zero and R1 and R2 are bonded directly to the same ring atom.
[0146] In yet another alternative embodiment of the synthetic
peptide amide, R1 is chosen from H, OH, --NH2, --COOH, --CH2COOH,
C1-C3 alkyl, amidino, C1-C3 alkyl-substituted amidino,
dihydroimidazole, D-Pro, D-Pro amide, and CONH2 and R2 is H,
--COOH, or C1-C3 alkyl.
[0147] Specific compounds of group (dd), as disclosed in U.S. Pat.
No. 7,713,937, include compounds 1-103 shown below:
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077## ##STR00078## ##STR00079## ##STR00080##
##STR00081##
[0148] For purposes of the compounds falling under group (dd), as
disclosed in U.S. Pat. No. 7,713,937, the term "synthetic peptide
amide" means a compound conforming to formula I, or a stereoisomer,
mixture of stereoisomers, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof. The designations Xaa.sub.1, Xaa.sub.2,
Xaa.sub.3, and Xaa.sub.4 represent D-amino acids in the synthetic
peptide amides of the invention. Stereoisomers of the synthetic
peptide amides conforming to formula I are limited to those
compounds having amino acids in the D-configuration where so
specified in Formula I. Stereoisomers of the synthetic peptide
amides include compounds having either a D- or L-configuration at
chiral centers other than the alpha carbons of the four amino acids
at Xaa.sub.1, Xaa.sub.2, Xaa.sub.3, and Xaa.sub.4. The term
`mixtures of stereoisomers` refer to mixtures of such
stereoisomers. As used herein `racemates` refers to mixtures of
stereoisomers having equal proportions of compounds with D- and
L-configuration at one or more of the chiral centers other than the
alpha carbons of Xaa.sub.1, Xaa.sub.2, Xaa.sub.3, and Xaa.sub.4
without varying the chirality of the alpha carbons of Xaa.sub.1,
Xaa.sub.2, Xaa.sub.3, and Xaa.sub.4.
[0149] The nomenclature used to define peptides of compounds (dd)
is specified by Schroder & Lubke, The Peptide's, Academic
Press, 1965, wherein, in accordance with conventional
representation, the N-terminus appears to the left and the
C-terminus to the right. Where an amino acid residue has isomeric
forms, both the L-isomer form and the D-isomer form of the amino
acid are intended to be covered unless otherwise indicated. Amino
acids are commonly identified herein by the standard three-letter
code. The D-isomer of an amino acid is specified by the prefix "D-"
as in "D-Phe" which represents D-phenylalanine, the D-isomer of
phenylalanine. Similarly, the L-isomer is specified by the prefix
"L-" as in "L-Phe-." Peptides are represented herein according to
the usual convention as amino acid sequences from left to right:
N-terminus to C-terminus, unless otherwise specified.
[0150] As used herein, D-Arg represents D-arginine, D-Har
represents D-homoarginine, which has a side chain one methylene
group longer than D-Arg, and D-Nar represents D-norarginine, which
has a side chain one methylene group shorter than D-Arg. Similarly,
D-Leu means D-leucine, D-Nle means D-norleucine, and D-Hle
represents D-homoleucine, D-Ala means D-alanine, D-Tyr means
D-tyrosine, D-Trp means D-tryptophan, and D-Tic means
D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. D-Val means
D-valine and D-Met means D-methionine. D-Pro means D-proline,
Pro-amide means the D- or L-form of proline amide. D-Pro amide
represents D-proline with an amide formed at its carboxy moiety
wherein the amide nitrogen may be alkyl substituted, as in
--NR.sub.aR.sub.b, wherein R.sub.a and R.sub.b are each
independently a C.sub.1-C.sub.6 alkyl group, or one of R.sub.a and
R.sub.b is --H. Gly means glycine, D-Ile means D-isoleucine. D-Ser
means D-serine, and D-Thr means D-threonine. (E)D-Ala means the
D-isomer of alanine which is substituted by the substituent (E) on
the .beta.-carbon. Examples of such substituent (E) groups include
tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
furyl, pyridyl, thienyl, thiazolyl and benzothienyl. Thus,
cyclopentyl-D-Ala means the D-isomer of alanine which is
substituted by cyclopentyl on the .beta.-carbon. Similarly,
D-Ala(2-thienyl) and (2-thienyl)D-Ala are interchangeable and both
mean the D-isomer of alanine substituted at the .beta.-carbon with
thienyl that is attached at the 2-ring position.
[0151] As used for the compounds of (dd), D-Nal means the D-isomer
of alanine substituted by naphthyl on the .beta.-carbon. D-2Nal
means naphthyl substituted D-alanine wherein the attachment to
naphthalene is at the 2-position on the ring structure and D-1Nal
means naphthyl-substituted D-alanine wherein the attachment to
naphthalene is at the 1-position on the ring structure. By
(A)(A')D-Phe is meant D-phenylalanine substituted on the phenyl
ring with one or two substituents independently chosen from halo,
nitro, methyl, halomethyl (such as, for example, trifluoromethyl),
perhalomethyl, cyano and carboxamide. By D-(4-F)Phe is meant
D-phenylalanine which is fluoro-substituted in the 4-position of
the phenyl ring. By D-(2-F)Phe is meant D-phenylalanine which is
fluoro-substituted in the 2-position of the phenyl ring. By
D-(4-Cl)Phe is meant D-phenylalanine which is chloro substituted in
the 4-phenyl ring position. By (.alpha.-Me)D-Phe is meant
D-phenylalanine which is methyl substituted at the alpha carbon. By
(.alpha.-Me)D-Leu is meant D-leucine which is methyl substituted at
the alpha carbon. The designations (B).sub.2D-Arg, (B).sub.2D-Nar,
and (B).sub.2D-Har represent D-arginine, D-norarginine and
D-homoarginine, respectively, each having two substituent (B)
groups on the side chain. D-Lys means D-lysine and D-Hlys means
D-homolysine. .zeta.-(B)D-Hlys, .epsilon.-(B)D-Lys, and
.epsilon.-(B).sub.2-D-Lys represent D-homolysine and D-lysine each
having the side chain amino group substituted with one or two
substituent (B) groups, as indicated. D-Orn means D-ornithine and
.delta.-(B).alpha.-(B')D-Orn means D-ornithine substituted with
(B') at the alpha carbon and substituted with (B) at the side chain
.delta.-amino group. D-Dap means D-2,3-diaminopropionic acid. D-Dbu
represents the D-isomer of alpha, gamma-diamino butyric acid and
(B).sub.2D-Dbu represents alpha, gamma-diamino butyric acid which
is substituted with two substituent (B) groups at the gamma amino
group. Unless otherwise stated, each of the (B) groups of such
doubly substituted residues are independently chosen from H-- and
C.sub.1-C.sub.4-alkyl. As used herein, D-Amf means
D-(NH.sub.2CH.sub.2-)Phe, i.e., the D-isomer of phenylalanine
substituted with aminomethyl on its phenyl ring and D-4Amf
represents the particular D-Amf in which the aminomethyl is
attached at the 4-position of the ring. D-Gmf means D-Amf(amidino)
which represents D-Phe wherein the phenyl ring is substituted with
--CH.sub.2NHC(NH)NH.sub.2. Amd represents amidino, --C(NH)NH.sub.2,
and the designations (Amd)D-Amf and D-Amf(Amd) are also
interchangeably used for D-Gmf. The designations Ily and Ior are
respectively used to mean isopropyl Lys and isopropyl Orn, wherein
the side chain amino group is alkylated with an isopropyl group.
Alkyl means an alkane radical which can be a straight, branched,
and cyclic alkyl group such as, but not limited to, methyl, ethyl,
propyl, isopropyl, cyclopropyl, butyl, t-butyl, sec-butyl, pentyl,
cyclopentyl, hexyl, cyclohexyl, cyclohexylethyl. C.sub.1 to C.sub.8
alkyl refers to alkyl groups having between one and eight carbon
atoms. Similarly. C.sub.1-C.sub.6 alkyl refers to alkyl groups
having between one and six carbon atoms. Likewise. C.sub.1-C.sub.4
alkyl refers to alkyl groups having between one and four carbon
atoms. By lower alkyl is meant C.sub.1-C.sub.6 alkyl, Me, Et, Pr,
Ipr, Bu, and Pn are interchangeably used to represent the common
alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, and pentyl,
respectively. Although the linkage for an alkyl group is typically
at one end of an alkyl chain, the linkage may be elsewhere in the
chain, e.g. 3-pentyl which may also be referred to as ethylpropyl,
or 1-ethylprop-1-yl. Alkyl-substituted, such as C.sub.1 to C.sub.6
alkyl-substituted amidino, indicates that the relevant moiety is
substituted with one or more alkyl groups.
[0152] Where a specified moiety of the compounds of group (dd) is
null, the moiety is absent and if such moiety is indicated to be
attached to two other moieties, such two other moieties are
connected by one covalent bond. Where a connecting moiety is shown
herein as attached to a ring at any position on the ring, and
attached to two other moieties, such as R.sub.1 and R.sub.2, in the
case where the connecting moiety is specified to be null, then the
R.sub.1 and R.sub.2 moieties can each be independently attached to
any position on the ring. The terms "heterocycle", "heterocyclic
ring" and "heterocyclyl" are used interchangeably herein and refer
to a ring or ring moiety having at least one non-carbon ring atom,
also called a heteroatom, which can be a nitrogen atom, a sulfur
atom, or an oxygen atom. Where a ring is specified as having a
certain number of members, the number defines the number of ring
atoms without reference to any substituents or hydrogen atoms
bonded to the ring atoms. Heterocycles, heterocyclic rings and
heterocyclyl moieties can include multiple heteroatoms
independently selected from nitrogen, sulfur, or oxygen atom in the
ring. Rings can be substituted at any available position. For
example, but without limitation, 6- and 7-membered rings are often
substituted in the 4-ring position and 5-membered rings are
commonly substituted in the 3-position, wherein the ring is
attached to the peptide amide chain at the 1-ring position. The
term "saturated" means an absence of double or triple bonds and the
use of the term in connection with rings describes rings having no
double or triple bonds within the ring, but does not preclude
double or triple bonds from being present in substituents attached
to the ring. The term "non-aromatic" in the context of a particular
ring refers to an absence of aromaticity in that ring, but does not
preclude the presence of double bonds within the ring, including
double bonds which are part of an aromatic ring fused to the ring
in question. Nor is a ring atom of a saturated heterocyclic ring
moiety precluded from being double-bonded to a non-ring atom, such
as for instance a ring sulfur atom being double-bonded to an oxygen
atom substituent. As used herein, heterocycles, heterocyclic rings
and heterocyclyl moieties also include saturated, partially
unsaturated and heteroaromatic rings and fused bicyclic ring
structures unless otherwise specified. A heterocycle, heterocyclic
ring or heterocyclyl moiety can be fused to a second ring, which
can be a saturated, partially unsaturated, or aromatic ring, which
ring can be a heterocycle or a carbocycle. Where indicated, two
substituents can be optionally taken together to form an additional
ring. Rings may be substituted at any available position. A
heterocycle, heterocyclic ring and heterocyclyl moiety can, where
indicted, be optionally substituted at one or more ring positions
with one or more independently selected substituents, such as for
instance, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, halo C.sub.1-C.sub.6 alkyl, optionally
substituted phenyl, aryl, heterocyclyl, oxo, --OH, --Cl, --F,
--NH.sub.2, --NO.sub.2, --CN, --COOH and amidino. Suitable optional
substituents of the phenyl substituent include for instance, but
without limitation, one or more groups selected from
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3alkoxy, halo
C.sub.1-C.sub.3alkyl, oxo, --OH, --Cl, --F, --NH.sub.2, --NO.sub.2,
--CN, --COOH and amidino. D-Phe and substituted D-Phe are examples
of a suitable amino acid for residue Xaa.sub.1 in Formula I. The
phenyl ring can be substituted at any of the 2-, 3-and/or
4-positions. Particular examples of permitted substitutions
include, for instance, chlorine or fluorine at the 2- or
4-positions. Also the alpha-carbon atom may be methylated. Other
equivalent residues which represent conservative changes to D-Phe
can also be used. These include D-Ala(cyclopentyl), D-Ala(thienyl),
D-Tyr and D-Tic. The residue at the second position, Xaa.sub.2 can
also be D-Phe or substituted D-Phe with such substitutions
including a substituent on the 4-position carbon of the phenyl
ring, or on both the 3- and 4-positions. Alternatively, Xaa.sub.2
can be D-Trp, D-Tyr of D-alanine substituted by naphthyl. The third
position residue, Xaa.sub.3 can be any non-polar amino acid
residue, such as for instance, D-Nle. D-Leu, (.alpha.-Me)D-Leu,
D-Hle, D-Met or D-Val. However, D-Ala(cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl) or D-Phe can also be used as Xaa.sub.3.
The fourth position residue Xaa.sub.4 can be any positively charged
amino acid residue, such as for instance, D-Arg and D-Har, which
can be optionally substituted with lower alkyl groups, such as one
or two ethyl groups. Alternatively, D-Nar and any other equivalent
residues can be used, such as, for instance, D-Lys or D-Orn (either
of which can be .omega.-amino group alkylated, for example by
methyl or isopropyl groups, or methylated at the .alpha.-carbon
group). Moreover, D-Dbu, D-4-Amf (which can be optionally
substituted with amidino), and D-Hlys are also suitable amino acids
at this position. The chemical designation
"tetrapeptide-[.omega.(4-amino-piperidine-4-carboxylic acid)]" is
used to indicate the aminoacyl moiety of the synthetic peptide
amides of the invention derived from 4-aminopiperidine-4-carboxylic
acid, wherein the nitrogen atom of the piperidine ring is bound to
the C-terminal carbonyl-carbon of the tetrapeptide fragment, unless
otherwise indicated.
[0153] Compounds of the group (dd) as disclosed in U.S. Pat. No.
7,713,937 contain one or more chiral centers, each of which has two
possible three-dimensional spatial arrangements (configurations) of
the four substituents around the central carbon atom. These are
known as "stereoisomers", and more specifically as "enantiomers"
(all chiral centers inverted) or "diastereoisomers" (two or more
chiral centers, at least one chiral center remaining the same). In
a specific embodiment of the invention, the amino acids which make
up the tetrapeptide backbone, Xaa.sub.1Xaa.sub.2Xaa.sub.3Xaa.sub.4
are specified to be D-amino acids i.e., the opposite configuration
to those generally found in mammals. Reference to stereoisomers of
the synthetic peptide amides concerns chiral centers other than the
alpha carbons of the D-amino acids which make up
Xaa.sub.1-Xaa.sub.4. Thus, stereoisomers of synthetic peptide
amides wherein each of Xaa.sub.1-Xaa.sub.4 are specified to be
D-amino acids, do not include L-amino acids or racemic mixtures of
the amino acids at these positions. Similarly, reference to
racemates herein concerns a center other than the alpha carbons of
the D-amino acids which make up Xaa.sub.1-Xaa.sub.4. Chiral centers
in the synthetic peptide amides of the invention for which a
stereoisomer may take either the R or S configuration include
chiral centers in the moiety attached to the carboxy-terminus of
Xaa.sub.4, and also chiral centers in any amino acid side chain
substituents of Xaa.sub.1-Xaa.sub.4. The synthetic peptide amides
can be used or prepared in alternate forms. For example, many
amino-containing compounds can be used or prepared as an acid salt.
Often such salts improve isolation and handling properties of the
compound. For example, depending on the reagents, reaction
conditions and the like, compounds such as the synthetic peptide
amides described herein can be used or prepared, for example, as
the hydrochloride or tosylate salts. The use of isomorphic
crystalline forms, all chiral and racemic forms, N-oxide, hydrates,
solvates, and acid salt, hydrates, are also contemplated to be
within the scope of the present invention. Certain acidic or basic
synthetic peptide amides of the present invention may exist as
zwitterions. All forms of these synthetic peptide amide compounds,
including free acid, free base and zwitterions, are contemplated
for use in the methods of the present invention. It is well known
in the art that compounds containing both amino and carboxyl groups
often exist in equilibrium with their zwitterionic forms. Thus, for
any compound described herein that contains, for example, both
amino and carboxyl groups, it will also be understood to include
the corresponding zwitterion.
[0154] In a preferred embodiment, the kappa agonist is a
peripherally restricted kappa agonist, including one or more of
ICI-204,448, Asimadoline, FE 200665, Fedotozine, any compound
disclosed in U.S. Pat. No. 7,713,937 (including but not limited to
Cara Therapeutics compound CR854), any peptide disclosed in U.S.
Pat. No. 5,965,701, combinations thereof or pharmaceutical salts
thereof. The theoretical benefits of a peripherally restricted
agent (be it a kappa agonist, NKB/NK3R antagonist, or a substance
P/NK1R antagonist) is that it would have only limited access to the
higher centers of the brain--areas controlling cognition, mood,
affect, movement, and integrative sensory function (which are
within the blood-brain barrier), but still have full access to
parts of the brain that are outside of the blood brain barrier,
including those areas of the hypothalamus that generate the VMS.
This novel approach would avoid the "side effects" of centrally
active agents (that cross the blood brain barrier), such as
dysphoria and euphoria, mental confusion, drowsiness, diminished
attentiveness, depression, etc. Since efficacious kappa agonists
produce compliance-limiting dysphoric responses when absorbed into
brain, agents that do not efficiently penetrate the blood-brain
barrier will produce the desired effect (e.g., reduction of
hot-flash symptoms) without adverse cognitive or mood
disturbance.
[0155] In another embodiment, the compound comprises a neurokinin
type 3 receptor antagonist (NK3R). Neurokinin B (NKB) acts directly
on KNDy neurons through NK3R to amplify their activity, and
likewise, NK3R antagonists block KNDy neuronal activity (Navarro et
al., Am J Physiol Endocrinol Metab. 2011 January; 300(1):E202-10;
Navarro et al., Endocrinology. 2011 November; 152(11):4265-75;
Ruiz-Pino F et al., 2012 October; 153(10):4818-29).
[0156] The term "antagonist" refers to a compound that can bind to
a neurokinin B receptor (NK3R) but has little or no functional
activity of its own at the receptor--thus disrupting, blocking or
otherwise interfering with the action of the naturally occurring,
endogenous ligand (i.e., NKB). An antagonist may be a ligand that
directly binds to the receptor. Alternatively, an antagonist may
combine with a receptor indirectly by, for example, (a) forming a
complex with another molecule that directly binds to the receptor,
or (b) otherwise results in the modification of another compound so
that the other compound directly binds to the NK3R. In other
embodiments, the term "antagonist" may include "inverse agonists",
which bind to NK3R and inhibit constitutive activity.
[0157] Any suitable NK3R antagonist can be used, including but not
limited to (or stereoisomers, mixture of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, solvates, acid salt
hydrates, N-oxides and isomorphic crystalline forms thereof):
[0158] (i) SB222200 (Available from, for example, Tocris
Bioscience)
##STR00082##
[0159] (ii) SR 142801 (Osanetant) (Available from, for example,
Axon Medchem, Germany)
##STR00083##
[0160] (iii) SB 218795--(Available from, for example, Tocris
Bioscience); (R)-[[2-Phenyl-4-quinolinyl)carbonyl]amino]-methyl
ester benzeneacetic acid
##STR00084##
[0161] (iv) SSR 146977 HCl (Available from, for example, Tocris
Bioscience);
N1-[1-3-[(3R)-1-Benzol-3-(3(3,4-dichlorophenyl)-3-piperidinyl]propyl]-4-p-
henyl-piperidinyl]-N,N-dimethylurea hydrochloride
##STR00085##
[0162] (v) AZD2624--(Astra Zeneca)
##STR00086##
and
[0163] (vi) Talnetant (SB 223412) (Available from, for example,
MedChem Express);
(S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamid-
e
##STR00087##
[0164] In another embodiment, the compound comprises a neurokinin
type 1 receptor antagonist (NK1R). Substance P acts on KNDy neurons
through NK1R to amplify their activity, and likewise, NK1R
antagonists block KNDy neuronal activity.
[0165] The term "antagonist" refers to a compound that can bind to
NK1R but has little or no functional activity of its own at the
receptor--thus disrupting, blocking or otherwise interfering with
the action of the naturally occurring, endogenous ligand (Substance
P). An antagonist may be a ligand that directly binds to the
receptor. Alternatively, an antagonist may combine with a receptor
indirectly by, for example, (a) forming a complex with another
molecule that directly binds to the receptor, or (b) otherwise
results in the modification of another compound so that the other
compound directly binds to the NK1R. In other embodiments, the term
"antagonist" may include "inverse agonists", which bind to NK1R and
inhibit constitutive activity.
[0166] Any suitable NK1R antagonist can be used, including but not
limited to (or stereoisomers, mixture of stereoisomers, prodrugs,
pharmaceutically acceptable salts, hydrates, solvates, acid salt
hydrates, N-oxides and isomorphic crystalline forms thereof):
[0167] (i) SR140333/Nolpitantium (Available from, for example,
Tocris Bioscience)
1-[2-[(3S)-3-(3,4-Dichlorophenyl)-1-[2-[3-(1-methylethoxy)phenyl]acetyl]--
3-piperidinyl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride
(peripherally restricted)
##STR00088##
[0168] (ii) L-733,060 hydrochloride(Available from, for example,
Tocris Bioscience)
(2S,3S)-3-[[3,5-bis(Trifluoromethyl)phenyl]methoxy]-2-phenylpiperidine
hydrochloride
##STR00089##
[0169] (iii) CP 96345: (Available from, for example, Tocris
Bioscience)
(2S,3S)-N-(-2-Methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]oc-
tan-3-amine
##STR00090##
[0170] (iv) Aprepitant:
5-([(2R,3S)-2-((R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorop-
henyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one (Merck, CO)
##STR00091##
[0171] (v) RP 67580 (Available from, for example, Tocris
Bioscience):(3aR,7aR)-Octahydro-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7--
diphenyl-4H-isoindol
##STR00092##
[0172] (vi) RPR-100893/dapitant (Rhone-Poulenc)
##STR00093##
[0173] (vii) CP-122721;
[(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidi-
ne]:
[0174] (viii) CJ-11974/ezlopitant (Pfizer):
(2S,3S)-2-benzhydryl-N-[(5-isopropyl-2-methoxy-phenyl)methyl]quinuclidin--
3-amine;
##STR00094##
[0175] (ix) L-754,274 (Merck);
[0176] (x) GR-203040: (Available from, for example, Sigma Aldrich)
((2S,3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine-
) (CAS Number 168398-02-5);
[0177] (xi) GR-205171/vofopitant (Glaxo) (Available from, for
example, BOC Sciences); CAS 168266-51-1; synonyms (a)
2S,3S)-N-{2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}-2-phe-
nyl-3-piperidinamine dihydrochloride; (b)-Piperidinamine,
N-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenyl]methyl]-2-ph-
enyl-, (2S,3S)-: (c)-Piperidinamine,
N-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenyl]methyl]-2-ph-
enyl-, (2S-cis)-
##STR00095##
[0178] (xii) LY-303870/lanepitant (Eli Lilly):
(R)-N-[2-[Acetyl[3H3][(2-methoxyphenyl)-methyl]amino]-1-(1H-indol-3-ylmet-
hyl)ethyl][1,4'-bipiperidine]-1'-acetamide
##STR00096##
[0179] (xiii) CP 99994 (Available from, for example, Tocris
Bioscience):
(2S,3S)-N-[(2-Methoxyphenyl)methyl]-2-phenyl-3-piperidinamine
dihydrochloride
##STR00097##
[0180] (xiv) FK 888 (Available from, for example, Tocris
Bioscience):
(4R)-4-Hydroxy-1-[(1-methyl-1H-indol-3-yl)carbonyl]-L-prolyl-N-methyl-3-(-
2-naphthalenyl)-N-(phenylmethyl)-L-alaninamide
##STR00098##
[0181] (xv) GR 82334: (Available from, for example, Tocris
Bioscience):
##STR00099##
[0182] (xvi) L 760735 (Available from, for example, Tocris
Bioscience):
5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluoro-
phenyl)-4-morpholinyl]methyl-N,N-dimethyl-1H-1,2,3-triazole-4-methanamine
hydrochloride
##STR00100##
[0183] (xvii) L-732,138 (Available from, for example, Tocris
Bioscience): N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl
ester
##STR00101##
[0184] (xviii) SDZ NKT 343 (Available from, for example, Tocris
Bioscience):
1-[[(2-Nitrophenyl)amino]carbonyl]-L-prolyl-N-methyl-3-(2-naphthalenyl)-N-
-(phenylmethyl)-L-alaninamide
##STR00102##
and
[0185] (xix) Spantide I (Available from, for example, Tocris
Bioscience): [D-Arg.sup.1,D-Trp.sup.7,9,Leu.sup.11]-Substance
P.
[0186] In one embodiment, the methods may combine use of two or
more compounds selected from the group consisting of kappa
agonists, NK3R antagonists, and NK1R antagonists. Thus, in a
further aspect, the present invention comprises a pharmaceutical
composition, comprising:
[0187] (1) two or more of a kappa agonist, an NK3R antagonist, an
NK1R antagonist, or salts thereof; and
[0188] (2) a pharmaceutically acceptable carrier.
[0189] The kappa agonist, NK3R antagonist, and/or NK1R antagonist
for use in the compositions of the invention can be any suitable
for a given purpose, including but not limited to any that are
disclosed above for use in the methods of the invention. In one
embodiment is the compounds are peripherally restricted.
[0190] Optionally, the compounds for use in the methods of the
invention (or the pharmaceutical compositions of the invention) can
be administered in combination with a second agent, including but
not limited to hormone therapy. In one non-limiting embodiment, the
short term estrogen therapy (2-3 months, for example) could be
administered to block VMS, followed by kappa agonist treatment to
hold the VMS down.
[0191] "Pharmaceutically acceptable" means approved or approvable
by a regulatory agency of the federal or state government, or
listed in the U.S. Pharmacopoeia or other generally recognized
pharmacopoeia for use in animals, and more particularly in humans.
It can be material which is not biologically or otherwise
undesirable, i.e., the material can be administered to an
individual without causing any undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained. The term
"pharmaceutically acceptable salt" of a compound means a salt that
is pharmaceutically acceptable and that possesses the desired
pharmacological activity of the parent compound. Such salts
include, for example, acid addition salts and base addition
salts.
[0192] In certain aspects, the present disclosure provides for a
pharmaceutical composition comprising the compounds of the present
disclosure together with one or more pharmaceutically acceptable
excipients or vehicles, and optionally other therapeutic and/or
prophylactic ingredients. Such excipients include liquids such as
water, saline, glycerol, polyethyleneglycol, hyaluronic acid,
ethanol, and the like.
[0193] The term "pharmaceutically acceptable vehicle" refers to a
diluent, adjuvant, excipient or carrier with which a compound of
the present disclosure is administered. "Pharmaceutically
acceptable carriers" for therapeutic use are well known in the
pharmaceutical art, and are described, for example, in Remington's
Pharmaceutical Sciences,18th Edition (Easton, Pa.: Mack Publishing
Company, 1990). For example, sterile saline and phosphate-buffered
saline at physiological pH can be used. Preservatives, stabilizers,
dyes and even flavoring agents can be provided in the
pharmaceutical composition. For example, sodium benzoate, sorbic
acid and esters of p-hydroxybenzoic acid can be added as
preservatives. In addition, antioxidants and suspending agents can
be used.
[0194] Suitable excipients for non-liquid formulations are also
known to those of skill in the art. A thorough discussion of
pharmaceutically acceptable excipients and salts is available in
Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.:
Mack Publishing Company, 1990). Additionally, auxiliary substances,
such as wetting or emulsifying agents, biological buffering
substances, surfactants, and the like, can be present in such
vehicles. A biological buffer can be any solution which is
pharmacologically acceptable and which provides the formulation
with the desired pH, i.e., a pH in the physiologically acceptable
range. Examples of buffer solutions include saline, phosphate
buffered saline, Tris buffered saline, Hank's buffered saline, and
the like.
[0195] Depending on the intended mode of administration, the
pharmaceutical compositions can be in the form of solid, semi-solid
or liquid dosage forms, such as, for example, tablets,
suppositories, pills, capsules, powders, liquids, suspensions,
creams, ointments, lotions or the like, preferably in unit dosage
form suitable for single administration of a precise dosage. The
compositions will include an effective amount of the selected drug
in combination with a pharmaceutically acceptable carrier and, in
addition, can include other pharmaceutical agents, adjuvants,
diluents, buffers, and the like. The present disclosure includes a
pharmaceutical composition comprising a compound of the present
disclosure including isomers, racemic or non-racemic mixtures of
isomers, or pharmaceutically acceptable salts or solvates thereof
together with one or more pharmaceutically acceptable carriers, and
optionally other therapeutic and/or prophylactic ingredients.
[0196] In general, the compounds are administered in a
therapeutically effective amount by any of the accepted modes of
administration. Suitable dosage ranges depend upon numerous factors
such as the severity of the disease to be treated, the age and
relative health of the subject, the potency of the compound used,
the route and form of administration, the indication towards which
the administration is directed, and the preferences and experience
of the medical practitioner involved. One of ordinary skill in the
art of treating such diseases will be able, without undue
experimentation and in reliance upon personal knowledge and the
disclosure of this application, to ascertain a therapeutically
effective amount of the compounds of the present disclosure for a
given disease.
[0197] Thus, the compounds can be administered as pharmaceutical
formulations including those suitable for oral (including buccal
and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or
parenteral (including intramuscular, intraarterial, intrathecal,
subcutaneous and intravenous) administration or in a form suitable
for administration by inhalation or insufflation. The preferred
manner of administration is intravenous or oral (or alternative
mucosal delivery, such as vaginal or nasal routes) using a
convenient daily dosage regimen which can be adjusted according to
the degree of affliction.
[0198] For solid compositions, conventional nontoxic solid carriers
include, for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, talc, cellulose,
glucose, sucrose, magnesium carbonate, and the like. Liquid
pharmaceutically administrable compositions can, for example, be
prepared by dissolving, dispersing, and the like, an active
compound as described herein and optional pharmaceutical adjuvants
in an excipient, such as, for example, water, saline, aqueous
dextrose, glycerol, ethanol, and the like, to thereby form a
solution or suspension. If desired, the pharmaceutical composition
to be administered can also contain minor amounts of nontoxic
auxiliary substances such as wetting or emulsifying agents, pH
buffering agents and the like, for example, sodium acetate,
sorbitan monolaurate, triethanolamine sodium acetate,
triethanolamine oleate, and the like. Actual methods of preparing
such dosage forms are known, or will be apparent, to those skilled
in this art; for example, see Remington's Pharmaceutical Sciences,
referenced above.
[0199] In yet another embodiment is the use of permeation enhancer
excipients including polymers such as: polycations (chitosan and
its quaternary ammonium derivatives, poly-L-arginine, aminated
gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid);
and, thiolated polymers (carboxymethyl cellulose-cysteine,
polycarbophil-cysteine, chitosan-thiobutylamidine,
chitosan-thioglycolic acid, chitosan-glutathione conjugates).
[0200] For oral administration, the composition will generally take
the form of a tablet, capsule, a softgel capsule or can be an
aqueous or nonaqueous solution, suspension or syrup. Tablets and
capsules are preferred oral administration forms. Tablets and
capsules for oral use can include one or more commonly used
carriers such as lactose and corn starch. Lubricating agents, such
as magnesium stearate, are also typically added. Typically, the
compounds of the present disclosure can be combined with an oral,
non-toxic, pharmaceutically acceptable, inert earlier such as
lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium pthosphate, calcium sulfate, mannitol, sorbitol
and the like. Moreover, when desired or necessary, suitable
binders, lubricants, disintegrating agents, and coloring agents can
also be incorporated into the mixture. Suitable binders include
starch, gelatin, natural sugars such as glucose or beta-lactose,
corn sweeteners, natural and synthetic gums such as acacia,
tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, and the like. Thus, for
example, capsules can be prepared by conventional procedures so
that the dosage unit is 100 mg of the compounds of the present
disclosure, 100 mg of cellulose and 10 mg of magnesium stearate. A
large number of unit capsules can also prepared by filling standard
two-piece hard gelatin capsules each with 100 mg of powdered active
ingredient, 150 mg of lactose, 50 mg of cellulose, and 10 mg
magnesium stearate. Or, tablets can be prepared by conventional
procedures so that the dosage unit is 100 mg of the compounds of
the present disclosure, 150 mg of lactose, 50 mg of cellulose and
10 mg of magnesium stearate. A large number of tablets can also be
prepared by conventional procedures such that the dosage unit was
100 mg of the compounds of the present disclosure, and other
ingredients can be 0.2 mg of colloidal silicon dioxide, 5 mg of
magnesium stearate, 250 mg of microcrystalline cellulose, 10 mg of
starch and 100 mg of lactose. Appropriate coatings can be applied
to increase palatability or delay absorption.
[0201] When liquid suspensions are used, the active agent can be
combined with any oral, non-toxic, pharmaceutically acceptable
inert carrier such as ethanol, glycerol, water, and the like and
with emulsifying and suspending agents. If desired, flavoring,
coloring and/or sweetening agents can be added as well. Other
optional components for incorporation into an oral formulation
herein include, but are not limited to, preservatives, suspending
agents, thickening agents, and the like.
[0202] Parenteral formulations can be prepared in conventional
forms, either as liquid solutions or suspensions, solid forms
suitable for solubilization or suspension in liquid prior to
injection, or as emulsions. Preferably, sterile injectable
suspensions are formulated according to techniques known in the art
using suitable carriers, dispersing or wetting agents and
suspending agents. The sterile injectable formulation can also be a
sterile injectable solution or a suspension in a nontoxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents that can be employed are water. Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils, fatty esters or polyols are conventionally
employed as solvents or suspending media. In addition, parenteral
administration can involve the use of a slow release or sustained
release system such that a constant level of dosage is
maintained.
[0203] Parenteral administration includes intraarticular,
intravenous, intramuscular, intradermal, intraperitoneal, and
subcutaneous routes, and include aqueous and non-aqueous, isotonic
sterile injection solutions, which can contain antioxidants,
buffers, bacteriostats, and solutes that render the formulation
isotonic with the blood of the intended recipient, and aqueous and
non-aqueous sterile suspensions that can include suspending agents,
solubilizers, thickening agents, stabilizers, and preservatives.
Administration via certain parenteral routes can involve
introducing the formulations of the present disclosure into the
body of a patient through a needle or a catheter, propelled by a
sterile syringe or some other mechanical device such as an
continuous infusion system. A formulation provided by the present
disclosure can be administered using a syringe, injector, pump, or
any other device recognized in the art for parenteral
administration.
[0204] Sterile injectable suspensions can be formulated according
to techniques known in the art using suitable carriers, dispersing
or wetting agents and suspending agents. The sterile injectable
formulation can also be a sterile injectable solution or a
suspension in a nontoxic parenterally acceptable diluent or
solvent. Among the acceptable vehicles and solvents that can be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils, fatty esters or polyols
are conventionally employed as solvents or suspending media. In
addition, parenteral administration can involve the use of a slow
release or sustained release system such that a constant level of
dosage is maintained. Preparations according to the present
disclosure for parenteral administration include sterile aqueous or
non-aqueous solutions, suspensions, or emulsions. Examples of
non-aqueous solvents or vehicles are propylene glycol, polyethylene
glycol, vegetable oils, such as olive oil and corn oil, gelatin,
and injectable organic esters such as ethyl oleate. Such dosage
forms can also contain adjuvants such as preserving, wetting,
emulsifying, and dispersing agents. They can be sterilized by, for
example, filtration through a bacteria retaining filter, by
incorporating sterilizing agents into the compositions, by
irradiating the compositions, or by heating the compositions. They
can also be manufactured using sterile water, or some other sterile
injectable medium, immediately before use.
[0205] The formulations can optionally contain an isotonicity
agent. The formulations preferably contain an isotonicity agent,
and glycerin is the most preferred isotonicity agent. The
concentration of glycerin, when it is used, is in the range known
in the art, such as, for example, about 1 mg/mL to about 20
mg/mL.
[0206] The pH of the parenteral formulations can be controlled by a
buffering agent, such as phosphate, acetate, TRIS or L-arginine.
The concentration of the buffering agent is preferably adequate to
provide buffering of the pH during storage to maintain the pH at a
target pH.+-.0.2 pH unit. The preferred pH is between about 7 and
about 8 when measured at room temperature.
[0207] Other additives, such as a pharmaceutically acceptable
solubilizers like Tween 20.RTM. (polyoxyethylene (20) sorbitan
monolaurate), Tween 40.RTM. (polyoxyethylene (20) sorbitan
monopalmitate). Tween 80.RTM. (polyoxyethylene (20) sorbitan
monooleate), Pluronic F68.RTM. (polyoxyethylene polyoxypropylene
block copolymers), and PEG (polyethylene glycol) can optionally be
added to the formulation, and can be useful if the formulations
will contact plastic materials. In addition, the parenteral
formulations can contain various antibacterial and antifungal
agents, for example, parabens, chlorobutanol, phenol, sorbic acid,
thimerosal, and the like.
[0208] Sterile injectable solutions can be prepared by
incorporating one or more of the compounds of the present
disclosure in the required amount in the appropriate solvent with
various of the other ingredients enumerated above, as required,
followed by filtered sterilization. Generally, dispersions are
prepared by incorporating the various sterilized active ingredients
into a sterile vehicle which contains the basic dispersion medium
and the required other ingredients from those enumerated above. In
the case of sterile powders for the preparation of sterile
injectable solutions, the preferred methods of preparation are
vacuum-drying and freeze-drying techniques which yield a powder of
the active ingredient plus any additional desired ingredient from a
previously sterile-filtered solution thereof. Thus, for example, a
parenteral composition suitable for administration by injection is
prepared by stirring 1.5% by weight of active ingredient in 10% by
volume propylene glycol and water. The solution is made isotonic
with sodium chloride and sterilized.
[0209] Alternatively, the pharmaceutical compositions of the
present disclosure can be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable nonirritating excipient which is solid at
room temperature but liquid at the rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0210] Pharmaceutical compositions for use in the methods of the
invention can also be administered by nasal aerosol or inhalation.
Such compositions are prepared according to techniques well-known
in the art of pharmaceutical formulation and can be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
propellants such as fluorocarbons or nitrogen, and/or other
conventional solubilizing or dispersing agents.
[0211] Preferred formulations for topical drug delivery are
ointments and creams. Ointments are semisolid preparations which
are typically based on petrolatum or other petroleum derivatives.
Creams containing the selected active agent, are, as known in the
art, viscous liquid or semisolid emulsions, either oil-in-water or
water-in-oil. Cream bases are water-washable, and contain an oil
phase, an emulsifier and an aqueous phase. The oil phase, also
sometimes called the "internal" phase, is generally comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol;
the aqueous phase usually, although not necessarily, exceeds the
oil phase in volume, and generally contains a humectant. The
emulsifier in a cream formulation is generally a nonionic, anionic,
cationic or amphoteric surfactant. The specific ointment or cream
base to be used, as will be appreciated by those skilled in the
art, is one that will provide for optimum drug delivery. As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and non-sensitizing.
[0212] Formulations for buccal administration include tablets,
lozenges, gels and the like. Alternatively, buccal administration
can be effected using a transmucosal delivery system as known to
those skilled in the art. The compounds of the present disclosure
can also be delivered through the skin or muscosal tissue using
conventional transdermal drug delivery systems, i.e., transdermal
"patches" wherein the agent is typically contained within a
laminated structure that serves as a drug delivery device to be
affixed to the body surface. In such a structure, the drug
composition is typically contained in a layer, or "reservoir,"
underlying an upper backing layer. The laminated device can contain
a single reservoir, or it can contain multiple reservoirs. In one
embodiment, the reservoir comprises a polymeric matrix of a
pharmaceutically acceptable contact adhesive material that serves
to affix the system to the skin during drug delivery. Examples of
suitable skin contact adhesive materials include, but are not
limited to, polyethylenes, polysiloxanes polyisobutylenes,
polyacrylates, polyurethanes, and the like. Alternatively, the
drug-containing reservoir and skin contact adhesive are present as
separate and distinct layers, with the adhesive underlying the
reservoir which, in this case, can be either a polymeric matrix, or
it can be a liquid or gel reservoir, or can take some other form.
The backing layer in these laminates, which serves as the upper
surface of the device, functions as the primary structural element
of the laminated structure and provides the device with much of its
flexibility. The material selected for the backing layer should be
substantially impermeable to the active agent and any other
materials that are present.
[0213] The compounds of the present disclosure can be formulated
for aerosol administration, particularly to the respiratory tract
and including intranasal administration. The compound will
generally have a small particle size for example of the order of 5
microns or less. Such a particle size can be obtained by means
known in the art, for example by micronization. The active
ingredient is provided in a pressurized pack with a suitable
propellant such as a chlorofluorocarbon (CFC) for example
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
The aerosol can conveniently also contain a surfactant such as
lecithin. The dose of drug can be controlled by a metered valve.
Alternatively the active ingredients can be provided in a form of a
dry powder, for example a powder mix of the compound in a suitable
powder base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The
powder carrier will form a gel in the nasal cavity. The powder
composition can be presented in unit dose form for example in
capsules or cartridges of e.g., gelatin or blister packs from which
the powder can be administered by means of an inhaler.
[0214] When desired, formulations can be prepared with enteric
coatings adapted for sustained or controlled release administration
of the active ingredient.
[0215] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0216] In other aspects, the present disclosure provides for kits
that can be used to perform the methods described herein. In
various aspects, the kits comprise the compounds of the present
disclosure in one or more containers. In some aspects, the kits
contain all of the components necessary and/or sufficient to
administer the compounds of the present disclosure to a subject,
including instructions for administering the compounds.
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EXAMPLES
[0258] Below are examples of specific embodiments for carrying out
the present disclosure. The examples are offered for illustrative
purposes only, and are not intended to limit the scope of the
present disclosure in any way.
1. Animal Studies Confirm Efficacy of a PRKA to Block GnRH/LH
Secretion
[0259] The deleterious effects associated with an acute loss of
circulating estradiol during the perimenopausal transition towards
menopause include an inability to properly thermoregulate and
therefore an inability to maintain a comfortable body temperature
in the majority of women. The inability of perimenopausal women to
thermoregulate properly is characterized by uncomfortable vasomotor
symptoms (VMS) including debilitating hot flashes followed by
chills, sweating and facial flushing. These VMS contribute to sleep
disruptions, irritability, anxiety and low mood. Although estrogen
therapy (ET) effectively reduces the occurrence and severity of
uncomfortable VMS, ET can pose significant health risks. Therefore,
we sought to investigate alternative therapies involving
peripherally-restricted kappa agonists (PRKAs), which pose
little/no side effects. Although the factors that initiate the
uncomfortable VMS during the acute loss of circulating estradiol
are not well understood, estrogen-sensitive circuits in the brain
clearly play a role--the estrogen-sensitive neurocircuitry of the
arcuate nucleus (ARC) within the hypothalamus is a possible
therapeutic target of PRKAs. Hot flashes in women occur in
coincidence with pulsatile LH secretion pulsatile LH release and
the temporally-matched menopausal VMS may be governed by the same
specialized neurons within the ARC--these specialized neurons
co-express kisspeptin, neurokinin B (NKB), type 3 NKB receptors
(NK3R), dynorphin, and substance P (so-called KNDy neurons). KNDy
neurons also express estrogen receptor alpha (ER.alpha.) and are
inhibited by estradiol.
[0260] We thus tested whether kappa opioid receptor agonists could
be used to treat hot flashes. We aimed to establish whether PRKA
administration decreases circulating LH levels in mice, a first
step in establishing whether this agent would likely act to inhibit
KNDy neurons in menopausal women to alleviate menopausal VMS.
[0261] Materials and Methods
[0262] Animals
[0263] Female mice (000664 C57BL/6J) were obtained from The Jackson
Laboratory (Sacramento, Calif., USA) at 8 weeks of age. All animals
were housed on a 12:12-h light-dark cycle (lights off at 1800) with
food and water available ad libitum. All experiments were conducted
in accordance with the National Institutes of Health (NIH) Animal
Care and Use Guidelines and with approval of the Animal Care and
Use Committee of the University of Washington.
[0264] Ovariectomies
[0265] Mice were ovariectomized 13 days prior to the experiment,
which occurred at approximately 11 weeks of age. Mice were
anesthetized with isoflurane and bilaterally ovariectomized (OVX).
Briefly, the animal's ventral skin was shaved and cleaned, and
small incisions were made in the skin and abdominal musculature.
The gonads were identified and excised, the abdominal muscle was
sutured, and the skin incision was closed with surgical clips.
[0266] Treatments and Experimental Design
[0267] Mice were injected i.p. (<500 .mu.l) with vehicle [0.9%
sterile saline (Hospira, Lake Forest, Ill., USA) with 3.6% sterile
DMSO (Sigma Aldrich, Inc., St. Louis, Mo., USA), n=7] or the
following doses of the PRKA, ICI204,448 hydrochloride (Tocris
Bioscience, Bristol, UK), diluted in sterile saline/DMSO: 0.1 mg/kg
(0.018% DMSO, n=6), 1 mg/kg (0.18% DMSO, n=4), 10 mg/kg, (1.8%
DMSO, n=5), or 20 mg/kg (3.6% DMSO, n=7). N.B. 1 mg/kg and 10 mg/kg
groups run in different experiment/assay. To assess the effects of
ICI204,448 hydrochloride on LH secretion, blood samples were
obtained 10 minutes prior to and 20 minutes after injection. Blood
collections were obtained via retroorbital bleeding
(.quadrature.250 .mu.l) of animals under isoflurane anesthesia.
Blood was centrifuged and the serum stored at -20.degree. C. until
it was assayed for LH via radioimmunoassay.
Results
[0268] We injected 3 groups of ovariectomized mice (n=6-7/group)
with the PRKA, ICI 204,448 hydrochloride (Tocris), i.p. as a High
Dose (20 mg/kg). Low Dose (0.1 mg/kg), or saline Vehicle. Blood
samples were taken ten minutes before and 20 minutes after
injection. A 2-way repeated measures analysis of variance of LH
yielded a significant treatment.times.time interaction (P<0.05),
and a Bonferroni Post-hoc test revealed that post injection. LH was
significantly decreased in the High Dose group vs. both Low Dose
and Vehicle groups (P<0.01 and P<0.001, respectively). (See
FIG. 2) These results suggest that KNDy neurons are a target of
PRKAs and provide proof of concept for utilizing such agents for a
treatment of VMS in perimenopausal women.
2. Using Kappa-Opioid Agonists to Treat Vasomotor Symptoms of
Menopause: Results from Rodent and Human Studies
[0269] Many kappa ligands including dynorphin have complicated
central effects on the brain: dysphoria, analgesia, stress-relief
effects (14-16). Such side effects make these agents less than
ideal for long-term use to control hot flashes. Thus, a
peripherally-restricted kappa-opioid receptor agonist that would
have access to the arcuate (infundibular) nucleus, which lies
outside the blood brain barrier, could be especially effective for
treating hot flashes. Such an agent would restrict activity of the
kisspeptin neurons, but avoid cognitive and extraneous undesirable
effects of kappa ligands on the central nervous system (CNS). Thus,
our first objective was to test the ability of one of these agents
(ICI 204,448 HCl) to block LH secretion in mice (see Example 1), as
proof of principle that such a technique could inhibit kisspeptin
neuronal activity, and thereby block hot flashes. Unfortunately,
none of the peripherally-restricted kappa agonists are approved for
clinical use. However, there are some other types of kappa agonists
that are approved for clinical use, including Talwin Nx
(pentazocine+naloxone). Talwin Nx does cross the blood brain
barrier and may have a psychotomimetic effect (17). However, this
compound could still have value for obtaining proof of principle
that inhibiting arcuate (infundibular) kisspeptin neurons can limit
hot flashes. We administered Talwin Nx in a short-term in-patient
setting to women suffering hot flashes and measured its ability to
attenuate hot flashes.
Results
Talwin Nx in Human
Methods and Experimental Design
[0270] Women ages 45-60, >6 months amenorrheic, with .gtoreq.6
mod-severe daily hot flashes were recruited and gave full consent
to participate in a double-blind study to test the effects of a
kappa agonist (pentazocine) on the frequency of hot flashes
(subjectively reported and verified by skin conductance changes).
Ten women were given oral placebo, 50/0.5 mg or 25/0.25 mg
pentazocine/naloxone, each therapy randomly assigned to be taken on
3 separate days over 8 hours. Skin conductance was
objectively-measured using the Bahr monitor. Analyses were
performed using Friedman ANOVA.
Radioimmunoassays (RIA)
[0271] All hormone assays were performed in duplicate by the
University of Virginia Ligand Assay Laboratory (Charlottesville,
Va.). Mouse LH Sandwich: Reportable Range: 0.04-37.4 ng/mL,
intra-assay coefficient of variation (CV) is 5% (2 assays). N.B. 1
mg/kg and 10 mg/kg groups run in different assay. All of the women
had circulating levels of FSH and estradiol (E.sub.2) indicative of
menopause: FSH>30 mIU/mL, with an average value of 81.5.+-.9.5
mIU/mL (reportable range: 0.1-170 mIU/mL) all women had E.sub.2
levels under 17 pg/nL, with 8 out of 9 women below the detectable
limit of the assay (reportable range: 123-1700.0 pg/nL).
[0272] Pentazocine and naloxone had modest, yet significant effect
on limiting the frequency of hot flashes (approximately a 20%
reduction; see FIG. 3). The main side effect was nausea. Addition
of naloxone can be presumed to have exerted no significant effects
following oral administration since the dose is biologically inert.
Naloxone was added to oral version of agent to prevent its abuse as
an i.v. substance of abuse.
REFERENCES FOR EXAMPLE 2
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[0293] The description of embodiments of the disclosure is not
intended to be exhaustive or to limit the disclosure to the precise
form disclosed. While specific embodiments of, and examples for,
the disclosure are described herein for illustrative purposes,
various equivalent modifications are possible within the scope of
the disclosure, as those skilled in the relevant art will
recognize.
[0294] All of the references cited herein are incorporated by
reference. Aspects of the disclosure can be modified, if necessary,
to employ the systems, functions and concepts of the above
references and application to provide yet further embodiments of
the disclosure. These and other changes can be made to the
disclosure in light of the detailed description.
[0295] Specific elements of any of the foregoing embodiments can be
combined or substituted for elements in other embodiments.
Furthermore, while advantages associated with certain embodiments
of the disclosure have been described in the context of these
embodiments, other embodiments may also exhibit such advantages,
and not all embodiments need necessarily exhibit such advantages to
fall within the scope of the disclosure. Accordingly, the
disclosure is not limited.
* * * * *