JP2022173240A5

JP2022173240A5 -

Info

Publication number: JP2022173240A5
Application number: JP2022141117A
Authority: JP
Filing date: 2022-09-06
Publication date: 2023-05-25
Anticipated expiration: 2034-07-16

Claims

A transdermal patch containing a topical composition comprising:
(1) a compound represented by formula (I) below, or a stereoisomer, polymorph or pharmaceutically acceptable salt thereof:

During the ceremony,
_R20 , _R21 _, _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 and _R36 is independently H or deuterium;
Z is -OH, _-OR11 , -N( _R11 ) _R12 , _-SR11 or _P1 ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkyl cycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
R ₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted hetero is selected from the group consisting of aryl, substituted arylalkyl, and substituted heteroarylalkyl;
or
R ₁₄ and R ₁₅ , together with the atoms to which they are attached, are unsubstituted or 1, 2 or 3 independently selected from the group consisting of halo, methyl and methoxy; may form a 5- to 7-membered ring incorporating two ring heteroatoms selected from N, O and S, substituted with substituents;
R ₁₈ and R ₁₉ are each independently hydrogen or alkyl, which alkyl is unsubstituted or halo, hydroxy, alkoxy, amino, thio, methylthio, -C(O)OH, - substituted with one substituent selected from the group consisting of C(O)O-(alkyl), _-CONH2 , aryl and heteroaryl, wherein said aryl or heteroaryl is unsubstituted or alkyl , halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy substituted with a substituent selected from the group;
R ₁₄ and R ₁₈ may together with the atoms to which they are attached form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may together with the atoms to which they are attached form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring; and
R ₁₅ and R ₁₉ may together with the atoms to which they are attached form a 5- to 7-membered ring;
and,
_R1 and _R2 are independently H or _P2 ,
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4; and
R ₁₄ is independently at each occurrence H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted aryl selected from the group consisting of alkyl, and substituted heteroarylalkyl;
(2) a penetration enhancer; and
(3) at least one of a lipophilic solvent, a formulation base, and a thickening agent;

With respect to the compound represented by formula (I),
(a) _R1 is _P2 and _R2 is H;
(b) _R1 is H and _R2 is _P2 , or
(c) _R1 is _P2 and _R2 is _P2 ;
A transdermal patch according to claim 1.

With respect to the compound represented by formula (I),
(a) _P2 is

or
(b) _P2 is

is
3. A transdermal patch according to claim 1 or 2.

With respect to the compound represented by formula (I),
(a) R ₂₀ -R ₃₆ are each hydrogen, or
(b) at least one of R ₂₀ -R ₃₆ is deuterium;
A transdermal patch according to any one of claims 1-3.

With respect to the compound represented by formula (I),
(a) Z is -OH;
(b) Z is -OR ₁₁ ;
(c) Z is -N( _R11 ) _R12 , or
(d) Z is _P1 ;
A transdermal patch according to any one of claims 1-4.

6. Any one of claims 1 to 5, wherein the compound represented by formula (I) is a compound represented by formula (IA) below, or a stereoisomer, polymorph or pharmaceutically acceptable salt thereof A transdermal patch according to paragraph:

During the ceremony,
Z is -OH, _-OR11 , or _P1 ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, or substituted is alkylcycloheteroalkyl;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
_R14 and _R15 are independently H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroaryl is selected from the group consisting of alkyl; or
R ₁₄ and R ₁₅ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
and,
_R1 and _R2 are independently H or _P2 ,
wherein at least one of _R1 and _R2 is _P2 , and _P2 is

is selected from the group consisting of:
R ₁₄ is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl be done.

Penetration enhancers include N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, sodium lauryl sulfoacetate, dimethyl sulfoxide, decyl methyl sulfoxide, laurocapram, pyrrolidone, surfactants, azone-like compounds, alcohols, polyethylene glycol, diethylene glycol monoethyl 7. The transdermal patch of any one of claims 1-6, selected from the group consisting of ethers, fatty thiols, fatty acids and fatty acid esters, and combinations thereof.

Lipophilic solvents include lipophilic alcohols, polyethylene glycol, diethylene glycol monoethyl ether, polysorbate, Labrasol®, fatty acid esters, diethyl sebacate, propylene glycol monocaprylate, propylene glycol laurate, mono- and diglycerides, medium chain triglycerides , caprylic/capric triglyceride, glyceryl monocaprylate, glyceryl mono-oleate, glyceryl mono-linoleate, glycerol oleate/propylene glycol, mineral and vegetable oils, and combinations thereof. 8. A transdermal patch according to any one of 7.

9. The transdermal patch of any one of claims 1-8, wherein the thickening agent is selected from the group consisting of glycerin, stearyl alcohol and polymers, and combinations thereof.

A transdermal patch according to any one of claims 1-9, wherein the topical composition further comprises a hydrophilic solvent.

A transdermal patch according to any one of claims 1-10, wherein the topical composition further comprises a solubilizer or an emulsifier.

A transdermal patch according to any one of claims 1-11, wherein the topical composition further comprises a microporous membrane, a skin adhesive and a backing material.

Hypertension, pulmonary hypertension, ischemic disease, heart failure, conditions requiring anticoagulation, thrombotic microangiopathy, central retinal vein occlusion, atherosclerosis, inflammatory disease, and cancer and other 13. A transdermal patch according to any one of claims 1 to 12 for use in treating a disease or condition selected from the group consisting of controlled cell proliferation conditions.

14. A transdermal patch for use according to claim 13, for use in treating pulmonary arterial hypertension.