Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-26
2003-03-18
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S370000, C514S371000
Reexamination Certificate
active
06534531
ABSTRACT:
BACKGROUND OF THE INVENTION
Alopecia is a common and distressing side effect of many chemotherapeutic agents. In addition, alopecia also occurs as a side effect of radiotherapy. As patients embark on new therapies, hair loss can induce a negative body image, alter interpersonal relationships, and often cause patients to reject potentially curative therapy.
Several preventive methods have been proposed. Those methods include scalp tourniquet, scalp hypothermia, or a combination of both, the rationale of which is to reduce the blood circulation during chemotherapy or radiotherapy. However, none of those methods has been shown to have a definitive protective effect, although undesirable effects, such as headaches, may arise.
More recently, Jiminez et al. (WO 93/00079), Lishko et al. (U.S. Pat. No. 5,753,263), and Davis et al. (WO 99/15500) have disclosed methods for preventing and treating chemotherapy- and radiotherapy-induced alopecia. However, the active agents disclosed in those applications and patent are structurally distinct from the compounds of the present invention.
In spite of the research that has been done in the past, and further in view of the limited success of currently available chemotherapy-induced alopecia treatments, there is a long-felt yet unmet need in the art for an improved treatment for alopecia induced by chemotherapy and radiotherapy.
Accordingly, it is an object of the present invention to provide a new method for the treatment of alopecia induced by chemotherapy and radiotherapy.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a method for preventing or treating alopecia induced by chemotherapy or radiotherapy which comprises administering to a mammalian specie in need thereof a therapeutically effective amount of a compound of formulas I or II
or enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. As used in formulas I and II, and throughout the specification, the symbols have the following meanings:
R is R
6
, COR
7
, CONH
2
, CONR
6
R
7
, COOR
6
or SO
2
R
6
;
R
6
is alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
R
7
is H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
where p is 0, 1 or 2; and q is 1 or 2 but both p and q cannot be 2, or
where i and j are each independently 0 or 1 but cannot both be 1, and Y is optionally substituted alkene, alkyne, or any 2 adjacent carbon atoms of a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;
R
8
is alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R
13
;
R
9
, R
10
, R
11
and R
12
are each independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, or hydroxy, alkoxy, amino, NR
14
R
15
, thio or alkylthio, provided that only one hydroxy, alkoxy, amino, NR
14
R
15
, thio or alkylthio group is bonded to any one carbon atom;
where Z is O, NR
18
or S;
R
16
and R
17
are each independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy, alkyloxycarbonyl, amino, NR
19
R
20
, carbamoyl, ureido, thio or alkylthio;
R
14
, R
15
, R
18
, R
19
and R
20
are each independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
R
1
and R
2
are each independently hydrogen, fluorine or alkyl;
R
3
is aryl or heteroaryl;
R
4
is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or
CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or
COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or
SO
2
-cycloalkyl, SO
2
-aryl, SO
2
-alkyl-cycloalkyl, SO
2
-alkyl-aryl, SO
2
-heteroaryl, SO
2
-alkyl-heteroaryl, SO
2
-heterocycloalkyl, SO
2
-alkyl-heterocycloalkyl; or
C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCN)NH-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocycloalkyl; or
C(NNO
2
)NH-alkyl, C(NNO
2
)NH-cycloalkyl, C(NNO
2
)NH-aryl, C(NNO
2
)NH-alkyl-cycloalkyl, C(NNO
2
)NH-alkyl-aryl, C(NNO
2
)NH-heteroaryl, C(NNO
2
)NH-alkyl-heteroaryl, C(NNO
2
)NH-heterocycloalkyl, C(NNO
2
)NH-alkyl-heterocycloalkyl; or
C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl; or
C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocycloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; or
C(NOR
21
)NH-alkyl, C(NOR
21
)NH-cycloalkyl, C(NOR
21
)NH-aryl, C(NOR
21
)NH-alkyl-cycloalkyl, C(NOR
21
)NH-alkyl-aryl, C(NOR
21
)NH-heteroaryl, C(NOR
21
)NH-alkyl-heteroaryl, C(NOR
21
)NH-heterocycloalkyl, C(NOR
21
)NH-alkyl-heterocycloalkyl;
R
5
is hydrogen or alkyl;
R
21
is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
m is an integer of 0 to 2; and
n is an integer of 1 to 3.
Advantageously, it has been found that the compounds of formulas I and II are useful for preventing or treating alopecia induced by chemotherapy or radiotherapy (radiation treatment).
DESCRIPTION OF THE INVENTION
The present invention provides methods for preventing and treating alopecia induced by chemotherapy or radiotherapy by administering to a mammalian specie, preferably a human, in need thereof a therapeutically effective amount of a compound of formula I or II.
The formula I compounds and methods for their preparation are described in WO 99/65884 and the formula II compounds and methods for their preparation are described in WO 99/24416, both of which are incorporated herein by reference thereto. Alternatively, compounds of formula II can be prepared by the processes discussed below.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
As used herein, the phrase “compounds of the invention” means, collectively, compounds falling within formulas I and II and pharmaceutically-acceptable salts, solvates, and hydrates thereof. Methods of salt formation, solvation, and hydrate formation are well known in the art. The invention also encompasses mixtures of stereoisomers of compounds of the invention. Stereoisomers include, but are not limited to, enantiomers, diastereomers, and racemates where the compound has one or more chiral centers. All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obta
Bol David K.
Kimball S. David
Webster Kevin R.
Bristol--Myers Squibb Company
Gerstl Robert
Patel Rena
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