EP1841406A2 - Methods and formulations - Google Patents

Abstract

The present invention describes methods and formulations using vitronectin receptor antagonists for the prevention of excessive scarring.

Description

METHODS AND FORMULATIONS

FIELD OF THE INVENTION

This invention relates to methods, topical formulations and methods of using topical formulations for the topical administration of vitronectin receptor antagonists for the prevention of excessive skin scarring.

BACKGROUND OF THE INVENTION lntegrins are a superfamily of heterodimeric transmembrane glycoproteins that are involved in adhesion as well as communication events. These heterodimeric transmembrane glycoproteins include α_vβ3 (the vitronectin receptor). The vitronectin receptor α_vβ3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The OyB₃ receptor expressed on the membrane of osteoclast cells mediates the adhesion of osteoclasts to the bone matrix, a key step in the bone resorption process. Ross, et al., J. Biol. Chem., 1987, 262, 7703. The α_vβ3 receptor expressed on human aortic smooth muscle cells mediates their migration into neointima, a process which can lead to restenosis after percutaneous coronary angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, Okada, et al., Am. J. Pathol., 1996, 149(1), 37 suggest that oc_vβ3 plays a role in vascular integrity and remodeling following focal ischemia within an infarcted area.

Additionally, it has been found that vitronectin receptor antagonists are useful in inhibiting adhesion formation, in particular, for the treatment of post-surgical adhesions US 2004/0142918.

Excessive scarring which can occur during the wound healing process can result in the formation of hypertrophic or keloid scars. Hypertrophic scars are those that stay within the boundaries of the initial wound while keloid scars spread from the initial wound and invade normal skin. Bayat A., McGrouther DA, Ferguson MWJ 2003 British Medical Journal, 326, 88-92; Brissett AE, Sherris DA 2001 Facial Plastic Surgery, 17 (4), 263-271. In addition to gross physical differences between hypertrophic scars and keloids, there are also microscopic differences in collagen organization and cellularity. Ehrlich HP, Desmouliere A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, Kapanci Y₁ Gabbiani G. 1994, American Journal of Pathology, 145(1 ), 105-113. Hypertrophic scars appear earlier than keloids: <4 weeks versus > 3 months to years after trauma. Hypertrophic scars may also slowly regress, though not disappear, while keloids continue to expand. Evidence in the literature indicates that hypertrophic scar formation may be related to the loss of control in the matrix production during the proliferation phase. Lygoe KA, Norman JT, Marshall JF, Lewis MP 2004 Wound Repair and Regeneration, 12, 461 -470. Fibroblast differentiation, survival and collagen production are the key steps involved in this process. Fibroblasts migrate in during the proliferation stage and begin to lay down collagen rich extracellular matrix. This migration is known to involve the expression of a number of integrins including αvβ3 and αvβ5. It has also been demonstrated that the adhesion of fibroblasts to the extracellular matrix via these integrins is at least partially responsible for triggering the synthesis of the collagen network. The antagonism of this binding would be expected to result in both a decreased fibrosis and a reduction in collagen synthesis and excessive scar formation. Av integrins are also involved in fibroblast differentiation to myofibroblasts. Blockade of αvβ3 and αvβ5 may also lead to decreased differentiation into myofibroblasts and a blunted response to growth factors such as transforming growth factor b (TGF-b). The importance of this blunted response is highlighted by the fact that TGF-b overproduction and a decrease in apoptosis of fibroblasts contribute to hypertrophic scar formation. Wang X, Smith P, Pu LLQ, Kim YJ, Ko F, Robson MC 1999 Journal of Surgical Research, 87, 194-200. Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Valle' CA, Roy M 2004, Journal of cellular Physiology, 198, 350-358. Recent research indicates that silicon sheets may reduce hypertrophic scars through an increase of basic fibroblast growth factor (bFGF) and a decrease in TGF-b rather than through direct pressure, increased oxygenation or increased hydration of the wound.

The management of hypertrophic scars and keloids is characterized by a wide variety of techniques. Many have been proven through extensive use over the last decades but few have been supported by prospective studies with adequate control groups and in some cases even safety data is missing. Nissen FB, Spauwen PH, Schalkwijk J, Kon M 1999, Plastic and Reconstructive Surgery, 104(5), 1435- 1458. Currently available treatments vary from surgery, pressure, corticosteroids, radiation, silicone, laser, cryotherapy, and experimental medications. With those therapies that have undergone clinical trials the results, particularly response rate and recurrence, are extremely variable. Multiple intralesional modalities have been tried including formalin, pepsin, HCI, oil of creosote, penacillamine, colchicines, 5- fluorouracil, bleomycin and interferon are a few. There are reports of successful animal studies with TGF modulators and with specific nontoxic inhibitors of collagen synthesis that can be applied locally. Early human trials using TGFs are in progress. Clearly there is still a deep and long felt need for new agents and formulations for the prevention of excess scar formation upon wound healing.

FIGURES

A brief description of the figures follows:

Fig 1. - in Vitro Percutaneous Absorption of Compound of Formula Ia* from Prototype Formulations Using Human Skin

SUMMARY OF THE INVENTION

The present invention provides methods of using vitronectin receptor antagonists for the prevention of excess scarring of skin, vitronectin receptor antagonist formulations suitable for topical application, and methods of using topical formulations of vitronectin receptor antagonists for the prevention of excess scarring of the skin in a mammal, in particular a human.

DETAILED DESCRIPTION OF THE INVENTION

In some embodiments, this invention describes a method of inhibiting excess scar formation on skin comprising the administration of a vitronectin receptor antagonist in a pharmaceutically acceptable formulation to a mammal in need thereof.

In some embodiments, the mammal to be treated is a human. In some embodiments, the methods of this invention comprise the topical administration of a vitronectin antagonist.

In some embodiments, the methods of this invention utilize a vitronectin receptor antagonist comprising a compound of formula I or II:

wherein: R is H, Ci._ealkyl, Ar, Het, or C_1-6 alkylaryl;

R is R , A-Crj-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4oxoalkenyl, A-C3-4oxoalkynyl, A-C-| ^aminoalkyl, A-C3.4aminoalkenyl, A-C3.4aminoalkynyl, unsubstituted or substituted by one or more of R¹O or R⁷; A is H, C3-6cycloalkyl, Het or Ar;

R⁷ is -COR⁸, -COCR'2R⁹, -C(S)R⁸, -S(O)_mOR', -S(O)mNR'R", -PO(OR'), -PO(OR')2, -NO2, or tetrazolyi; each R8 independently is -OR¹, -NR¹R", -NR'Sθ2R', -NR¹OR¹, or -OCR'2CO(O)R';

R9 is -OR¹, -CN, -S(O)rR\ -S(O)_mN(R')2, -C(O)R", C(O)N(R')2, or -CO2R';

R¹O is H, halo, -OR11 , -CN, -NR¹R¹¹, -NO2, -CF3, CF3S(O)_r, -CO2R¹, -CON(R')2, A-Co-6alkyl-, A-Ci -βoxoalkyl-, A-C2-6alkenyI-, A-C2-6alkynyl-, A-Crj-6alkyloxy-, A-Crj-βalkylamino- or A-Crj-6alkyl-S(0)r-;

R^{1 1} is R', -C(O)R¹, -C(O)N(R¹J₂, -C(O)OR', -S(O)_mR', or -S(O)_mN(R¹)₂;

-A-

W is -(CH Rg)₃-U-(CH R9)b-;

U is absent or is CO, CRg₂, C(=CRg₂), S(O)_k> O, NR9, CR9OR9, CRg(OR^k)CR9₂, CR92CR9(OR^k), C(O)CR9₂, CRg₂C(O)₁ CONR', NR'CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR9, NRgC(S), S(O)₂NRg₁ NR9S(O)₂ N=N, NR9NRg,

NRgCRg₂₁ CRg₂NRg₁ CRg₂O₁ OCRg₂, c≡c Or CRg=CRg; G is NRe, S or O;

Rg is H₁ C-j.galkyl, Het-Crj-galkyl, C3-7cycloalkyl-Cn-6^a'kyl or Ar-Crj-6alkyl; R^k is R9, -C(O)R9, or -C(O)OR^f;

R' is H, C-j _galkyl, Het-C_υ-6^alkyl, C3-7cycIoalkyl-Co-6^alkyl, Ar- Co-6^a"<yl, or C-|.galkyl substituted by one to three groups chosen from halogen, CN, NRg₂, ORg, SR9, CO₂R9, and CON(Rg)₂;

R^f is H, Chalky! or Ar-Co-6^aIM;

R^Θ is H, C-|_galkyl, Ar-Co-galkyl, Het-Co-6^a'kyl. Cs-ycycloalkyl-Co-βalkyl, or (CH₂)_kCO₂Rg;

R^ and R^c are independently selected from the group consisting of H, C-\. øalkyl, Ar-Co-6a'kyl, Het-Co-6^alkyl, Cs-ecycloalkyl-Co-θalkyl, halogen, CF3, OR^f, S(O)_kR^f, COR^f, NO₂, N(R^f)_2j CO(NR^f)₂, and CH₂N(R^f)₂; or R^b and R^c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, C-^alkyl, 0R^f, S(O)_kR^f, COR^f, CO₂R^f, OH, NO₂, N(R^f)_2j CO(NR^f)₂, and CH₂N(R^f)₂ and methylenedioxy; Q^"1 , Q², Q³ and Q⁴ are independently N or C-Ry, provided that no more than one of Q¹ , Q², Q³ and Q⁴ is N;

R' is H, C-i-βalkyl, Ar-Crj-6alkyl or C₃-6cycloalkyl-Co-6alkyl; R" is R¹, -C(O)R¹ or -C(O)OR¹; R"' is H, C-μgalkyl, Ar-Co-_βalkyl, Het-Cn-6alkyl, C3-6cycloalkyl-Co_6alkyl, halogen, CF₃, 0R^f, S(O)|<R^f, COR^f, NO₂, N(R^f)₂, CO(NRf)₂, or CH₂N(R^f)₂;

Ry is H, halo, -0R9, -SR9, -CN, -NR9R^k, -NO₂, -CF₃, CF₃S(O)_n -CO₂R9, -C0R9, -CONR9₂, or C-|-6alkyl unsubstituted or substituted by halo, -0R9, -SR9, -

CN, -NR9R", -NO₂, -CF₃, R¹S(O)₁--, -CO₂Rg, -CORg, or -CONR9₂; a is O₁ 1 or 2; b is 0, 1 or 2; k is O, 1 or 2; m is 1 or 2; r is O, 1 or 2; s is 0, 1 or 2; u is O or 1; and v is O or 1 ; or a compound of formula Il

wherein

Ai is C or N;

E is a five- or six-membered heteroaromatic or six-membered aromatic ring optionally substituted by R3^* or R^4*;

X1-X² is CHR1^*-CH, CR1^*=C, NR1^*-CH, S(O)_U*-CH, or 0-CH; X³ is CRδ'Rδ^1*, NR5^*, S(O)₁₁* or O;

R'^* is H, Ci_-6 alkyl, Ar, Het, or C_1-6alkylaryl; R"* is R'^*, -C(O)R¹* or -C(O)ORs*; R'"^* is Cl -βalkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl; R1^* is H, C-|-6alkyl, or Ar-Co-4alkyl;

R2^* is -OR^1*, -NR'^*R"^*, -NR'^*Sθ2R"^!*, -NROR'^*, -OC(R¹^C(O)OR^1*, - OC(R'^*)2θC(O)-R^1*, -OC(R'^*)2C(O)N(R^1*)2, CF3 or COC(R^)₂R²'^*;

R2'^* is -OR^1*, -CN, -S(O)_r*R'^*, S(O)2N(R'^*)2, -C(O)R^1*, C(0)N(R'^*)2 or - CO2R^1*;

R5^* and PS'^* are independently H, Ci -galkyl, C3-7cycloalkyl-Co-4alkyl or Ar- Co-4alkyl;

R6^* is W-(C(R^1*)2)q^*-Z^*-(CR'^*Ri0^*)_r*-U^*-(C(R^1*)2)s*-V^*- or W'^*-(C(R'^*)2)q*- U^*-(C(R'^*)₂)_S ^*-; R3^*, R4^* and R7^* are independently H, halo, -0R12^*, -SR12^*, -CN, -

NR'^*R12^*, -NO2, -CF3, CF3S(O)_r*-, -CO2R^1*, -CON(R'*)2, Ri4^*-Cθ-6_alkyl-, R14^*- Ci-6oxoalkyl, Ri4^*-C2-6alkenyh Ri4^*-c₂-6alkynyl, Ri4^*-Co-6alkyloxy-, R14^*-CO- 6alkylamino or Ri4^*-Cn-6alkyl-S(O)_r*-;

R8^* is R¹*, C(O)R¹*, CN, NO2, Sθ2R'*or C(O)OR5^*; R9^* is R^1*, -CF3, -SR^1*, or -OR^1*;

R1O^* is H, C-|-4alkyl or -NR'*R"*;

R12^* is R^1*, -C(O)R^1*, -C(O)N(R'^*)2, -C(O)OR5^*, -S(0)m*R'^* or S(O)2N(R'*)2;

R14^* is H, C3-6cycloalkyl, Het or Ar;

R^15* is H, Ci-ioalkyl, Cs-ycycloalkyl-Co-salkyl or Ar-Crj-βalkyl; U^* and V^* are absent or are independently CO, C(R'^*)2, C=C(Ri 5^*)₂, S(O)_n*,

O, NR15^*, CRiδ'ORiδ^*, CR'*(OR"^*)CR^1*2, CR^CR¹⁺(OR"*), C(0)C(R'*)2, C(R15^*)₂C(O), CONR15^*, NR15^*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5^*, NR15^*C(S), SO2NR15^*, NR15^*SO2, N=N, NR15^*NR15^*, NR15^*C(R15^*)_2I NR15*C(R15*)_2J C(R15^*)₂O, OC(R15^*)₂₎ C≡C, CR15^*=CR15^*, Het, or Ar, provided that U* and V* are not simultaneously absent;

W^* is R'^*R"^*N-, R'^*R"^*NR'^*N-, R'^*R"^*NR"^*NCO-, R^1*2NR'^*NC(=NR'^*)-, R^1*0NR'^*C(=NR¹*)-,

.

W* is

Q* is NR'^*, 0 or S;

Ra^* is H, C-|-6alkyl, Ar-Co-6a"<yl, Het-Co-6alkyl, or Cs-Qcycloalkyl-Co-βalkyl, halogen OR^"!^*, SR1^*, COR1^*, OH, NO2, N(R1^*)₂₎ CO(NRi ^*)2, CH₂N(Ri ^*)_2;

Rb^* and Rc^* are independently selected from the group consisting of H, Ci- βa'kyl. Ar-Co-6^alM. Het-Co-6alkyl, or Cs-βcycloalkyl-Co-βalkyl, halogen, OR1^*, SR1^*, COR1^*, OH, NO₂, N(R1^*)₂, CO(NR1^*)_2> CH₂N(R1 ^*)_2J or Rb^* and Rc^* are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci^alkyl, OR1^*. SR1^*, COR1 ^*, OH₁ NO₂, N(R1^*)₂, CO(NRi ^*)_2J CH₂N(Ri ^*)₂, CN₁ or R"*R'^*NC(=NR'^*)-; X* is N=CR¹, C(O) or O;

Y* is absent, S or O;

Z* is (CH₂)t*, Het, Ar or C3-7cycloalkyl;

M* is 1 or 2;

N* is 0, 1 , 2, or 3; q* is 0, 1 , 2, or 3; r^* is 0, 1 or 2; s* is 0, 1 or 2; t* is 0, 1 or 2; u* is 0, 1 or 2; v^* is 0 or 1 ; and w* is 0 or 1 ; or or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of formula I is Ia

Ia

wherein R is H, Ci_-6alkyl, Ar, Het, Ci_-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of formula Ia is Ia*

Ia* or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula Il is Ha

Ha wherein R is H, C_1-6alkyl, Ar, Het, C_1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of formula Na is Ha^*

(Ha*)

In some embodiments, this invention describes a method of inhibiting excess hypertrophic scar formation on skin comprising the topical administration of a pharmaceutically acceptable topical formulation comprising a carrier and a compound of formula I, II, Ia, Ha, Ia^*, or Ha*, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention describes a formulation suitable for the topical administration of a compound of formula I or II,

(I) wherein:

R is H, Ci.₆alkyl, Ar, Het, or C_t.₆alkylaryl;

R is R , or A-Crj-4 alkyl-, A-C2-4alkenyl-, A-C2-4alkynyl-, A-C3-4θxoalkenyl-, A-C3-4oxoalkynyl-, A-Ci_4aminoalkyl-, A-C3_4aminoalkenyl-, A-C3_4aminoalkynyl-, optionally substituted by any accessible combination of one or more of R¹ ° or R⁷; A is H, C3-6cycloalkyl, Het or Ar;

R7 is -COR⁸, -COCR'2R⁹, -C(S)R⁸, -S(O)mOR', -S(OJmNR¹R", -PO(OR¹), -P0(0R')2, -Nθ2, or tetrazolyl; each R⁸ independently is -OR¹, -NR¹R", -NR'SO2R', -NR¹OR¹, or -OCR'2CO(O)R";

R9 is -OR¹, -CN, -S(O)_rR', -S(O)_nN(R^, -C(O)R¹, C(O)N(R')₂, Or -CO₂R¹;

R¹⁰ is H, halo, -OR^{1 1} , -CN, -NR¹R^{1 1} , -NO₂, -CF3, CF3S(0)_r, -CO₂R', -C0N(R')2, A-Co-6alkyl-, A-Ci _6oxoalkyl-, A-C₂-6alkenyl-, A-C₂-6alkynyl-, A-Co-6alkyloxy-, A-Co-6^alkylamino- or A-Crj-6^a|kyl-S(0)r-;

R^{1 1} is R¹, -C(O)R¹, -C(0)N(R')2, -C(O)OR", -S(O)_nR', or -S(0)mN(R')₂;

W is -(CHRg)a-U-(CHR9)b-; U is absent or is CO, CR^Q ₂, C(=CR9₂), S(0)_k, 0, NR9, CR9OR9,

CRg(ORk)CRg₂, CRg₂CRg(ORk), C(O)CR9₂, CRg₂C(O), CONR', NR'CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRg, NRQC(S), S(O)₂NRS, NRSS(O)₂ N=N₁ NRSNRS, NRSCRg₂, CRQ₂NRg, CRS₂O, OCR^Q ₂, C≡C Or CRg=CRS;

G is NR^e, S or O;

RS is H, C-] _@alky[, Het-Co-galkyl, C₃-7cycloalkyl-Co-6alkyl or Ar-Crj-6alkyl; R^k is RS, -C(O)RQ, or -C(O)OR^f;

R' is is H, C-|_6alkyl, Het-Co-6^a'kyl, C3-7cycloalkyl-Cø_.-6alkyl, ^Ar" Co-galkyl, or C-j_5alkyl substituted by one to three groups chosen from halogen, CN, NRS₂, ORS, SRS, CO₂RS, and CON(RS)₂;

Rf is H, C-] .øalkyl or Ar-Co-_βalkyl; R^e is H₁ Ci-ρalkyl, Ar-Co-βalkyl, Het-Co-βalkyl, C3-7cycloalkyl-Co-6alkyI_> ^or

(CH₂)_kCO₂RS;

Rb and R^c are independently selected from the group consisting of H, C-_] . galkyl, Ar-Co-6alkyl, Het-Crj-6alkyl, Cs-δcycloalkyl-Co-ealkyl, halogen, CF3, OR*,

S(O)_kRf, COR^f, NO₂, N(Rf)₂, CO(NR^f)₂, CH₂N(R^f)₂; or Rb and R° are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from the group consisting of halogen, CF₃, C-|_4alkyl, 0R^f, S(0)_kR^f, C0R^f, C0₂R^f, OH, NO₂, N(R^f)_2i CO(NR^f)₂, CH₂N(Rf)₂ and methylenedioxy;

Q¹ , Q², Q³ and Q⁴ are independently N or C-RY, provided that no more than one of Q¹ , Q², Q³ and Q⁴ is N;

R' is H, Ci-6alkyl, Ar-Crj-βalkyl or C3-6cycloalkyl-Cn,-6alkyl;

R" is R¹, -C(O)R¹ or -C(O)OR¹;

R'" is H, Chalky], Ar-Co-βalkyl, Het-Co-βalkyl, C3-6cycloalkyl-Cn_.-6alkyl, halogen, CF₃, OR^f, S(O)_kR^f, C0R^f, NO₂, N(R^f)_2j CO(NRf)₂, or CH₂N(Rf)₂; Ry is H, halo, -ORS, -SRS, -CN, -NRSRk, __No₂, -CF₃, CF₃S(O)_n -CO₂RS,

-CORS, -CONRS₂, or C-|-6alkyl optionally substituted by halo, -ORS, -SRS, -CN,

-NRSR", -NO₂, -CF₃, R¹S(O)_n -CO₂RS, -CORS or -CONRS₂; a is 0, 1 or 2; b is 0, 1 or 2; k is 0, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is O, 1 or 2; u is 0 or 1 ; and v is 0 or 1 ; or a compound of formula Il

(H) wherein

A-| is C or N;

E is a five- or six-membered heteroaromatic or six-membered aromatic ring unsubstituted or substituted by R3^* or R4^*;

X1-X2 is CHR1 ^*-CH, CR1 ^*=C, NR1^*-CH, S(O)_U*-CH or O-CH; X3 is CR5^*R5'^*, NR5^*, S(O)_U* or O;

R'^* is H, C_1-6alkyl, Ar, Het, or C_1-βalkylaryl;

R"* is R¹*, -C(O)R¹* or-C(O)OR5*;

R'"* is Ci-6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Cn-4alkyl;

R1^* is H, Ci-6alkyl, or Ar-Co-4alkyl; R2^* is -OR^1*, -NR^R"^*, -NR'^*Sθ2R'"*, -NROR^1*, -OC(R¹^C(O)OR'^*, -

OC(R'^*)2θC(O)-R'^*, -OC(R'^*)2C(O)N(R'^*)2, CF3 or COC(R¹^R²'^*;

R2'^* is -OR^1*, -CN, -S(O)_r*R'^*, S(O)2N(R'^*)2, -C(O)R^1*, C(O)N(R'^*)₂ or - CO2R^1*;

R5^* and R5'^* are independently H, Ci _6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar- Cf>4alkyl;

R6^* is W*-(C(R'*)2)q*-Z*-(CR"*RiO^*)_r*_j -U*-(C(R'*)2)s*-V*-, or W'^*-(C(R'*)2)q*- U^*-(C(R^1*)2)s^*-;

R3^*, R4^* and R7^* are independently H, halo, -OR12^*, -SR12^*, -CN, -

NR'*R12^*, -NO2, -CF3, CF3S(O)_r*-, -CO2R¹*, -CON(R'*)2, Ri4^*-Cθ-6_a|ky|-, R14^*. Ci -6oxoalkyl, Ri4^*-c₂-6alkenyl-, Ri4^*-C2-6alkynyl, Ri4^*-Co-6alkyloxy-, R14^*-C_O- βalkylamino or R14^*-Cn-6alkyl-S(O)_r*-;

R8^* is R¹*, C(O)R¹*, CN, NO₂, SO₂R'^*or C(O)OR5^*;

R9^* is R¹*, -CF3, -SR'^*, or -OR^1*;

R1O^* is H, Ci-4alkyl or -NR'*R"*; R12^* is R^1*, -C(O)R'^*, -C(O)N(R'^*)2, -C(O)OR5^*, -S(0)_m*R'^* or S(O)₂N(R'^*)₂;

R14^* is H, C3-6cycloalkyl, Het or Ar;

R15^* is H, Cl -1 oalkyl, C3-7cycloalkyl-Co-8all<yl or Ar-Co-8alkyl;

U^* and V* are absent or are independently CO, C(R'^*)2, C=C(Ri 5^*)₂, S(O)_n*. O, NR15^*, CR15-OR15^*, CR"^*(OR"*)CR'^*2, CR'^*2CR'^*(OR"^*), C(O)C(R'^*)2, C(R15^*)₂C(O), CONR15^*, NRi 5^*C0, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5^*, NR15^*C(S), SO₂NRi 5^*, NR15^*SO_2> N=N, NR15^*NR15^*, NR15^*C(R15^*)_2J NR15^*C(R15^*)₂₎ C(R15^*)₂O, OC(Ri 5^*)₂₎ C≡C, CR15^*=CR15^*, Het, or Ar, provided that U* and V^* are not simultaneously absent;

W* is R'*R"*N-, R'*R"*NR'*N-, R'*R"*NR'^*NC0-, R'^* ₂NR'^*NC(=NR^1*)-, R'*0NR'*C(=NR'*)-,

.

W* is

Q^* is NR¹*, O or S;

R^a* is H, Ci-βalkyl, Ar-Co-6^a|W> Hθt-Co-6alkyl, or C3-6cycloalkyl-Cn-6alkyl> halogen OR1^*, SR1^*, COR1 ^*, OH, NO2, N(R1^*)₂, CO(NRi ^*)₂, CH2N(R1^*)2;

Rb^* and Rc^* are independently selected from H, C-|-6alkyl, Ar-Crj-6alkyl, Het- Co-βalkyl, or Cs-βcycloalkyl-Co-βalkyl, halogen, OR1^*. SR1^*. COR1^*, OH, NO2, N(R^{1 *})2_> CO(NRi ^*)2, CH2N(R1 ^*)2, or Rb^* and Rc^* are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci- ₄alkyl, OR1^*, SR1^*, COR1^*, OH, NO₂, N(R1^*)2, CO(NRi ^*)_2> CH2N(R1^*)₂, CN, or R"*R'*NC(=NR'*)-;

X^* is N=CR¹, C(O) or O; Y^* is absent, S or O; Z^* is (CH2)f, Het, Ar or C3-7cycloalkyl; M^* is 1 or 2;

N^* is O, 1 , 2, or 3; q* is θ, 1 , 2, or 3; r^* is 0, 1 or 2; s* is O, 1 or 2; t* is 0, 1 or 2; u^* is 0, 1 or 2; v* is 0 or 1 ; and w^* is 0 or 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein the formulation comprises from about 0.01 % to 50% w/w of the compound of formula I or Il and from about 0.5% to 99% of one or more penetration enhancers. In some embodiments of the formulations of this invention, the compound of formula I is Ia,

wherein R is H, d^alkyl, Ar, Het, C^salkylaryl; or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Ha,

Na wherein R^2* is H, C_1-6alkyl, Ar, Het, C_1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments of the formulations of this invention, the compound of formula Ia is 1a*,

(Ia*) or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Na^*,

(Ha*)

or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, this invention describes a formulation comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha^*, wherein the compound of formula I, II, Ia, Ha, Ia^*, or Ha*, comprises from about O.01 % to 10% w/w of the formulation.

In some embodiments, this invention describes a formulation suitable for topical administration comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha* and further comprising one or more penetration enhancers wherein the penetration enhancer or enhancers comprise from about 0.5% to 40% w/w of the formulation. In some embodiments, this invention describes a formulation suitable for topical administration comprising a compound of formula I, II, Ia, Ha, Ia^*, or Ha^* and further comprising one or more penetration enhancers wherein the penetration enhancer or enhancers comprise from about 0.5% to 25% w/w of the formulation.

In some embodiments, the formulations of this invention comprise a penetration enhancer selected from a group consisting of propylene glycol, benzyl alcohol, polyethylene glycols, dimethyl isosorbide, diethylene glycol monomethyl ether, macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers, laurocapram, and caprylocaproyl macrogol-8 glycerides, or combinations thereof.

In some embodiments, formulations of this invention comprise a penetration enhancer or enhancers wherein said penetration enhancer or enhancers comprises propylene glycol. In some embodiments, formulations of this invention comprises a penetration enhancer or enhancers wherein said penetration enhancer or enhancers comprises at least one surfactant.

In some embodiments, the formulations of this invention have a pH of greater than about 7. In some embodiments, the formulations of this invention have a pH of greater than 8. In some embodiments, this invention describes a formulation having a pH of from about 8.5 to 9.5.

In some embodiments, the formulations of this invention comprise from about 1 % to 45% w/w of a buffer having a pH in the range of from 8 to 11. In some embodiments, the formulations of this invention comprise from about

25% to 75% w/w of one or more waxes, ointments, or bases, or combinations thereof.

In some embodiments, the formulations of this invention comprise from about 4% to 12% w/w of one or more emollients. In some embodiments, the formulations of this invention comprise from about

0.5% to 10% w/w of a surfactant.

In some embodiments, the formulations of this invention comprise from about 0.001 % to 2% of one or more antioxidants.

In some embodiments, the formulations of this invention comprise from about 0.05% to 5% of a compound of formula I, II, Ia, Ha, Ia*, or Ha*; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 1.0% to 25% of one or more penetration enhancers; from about 0.01% to 1 % of one or more antioxidants; and from about 5% to 35% w/w of a pH 9-11 buffer. In some embodiments, the formulations of this invention comprise from about

0.1 % to 2% w/w of the compound of formula I, II, Ia, Ha, Ia*, or Ha*; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 4.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.5% of one or more antioxidants; and from about 10% to 30% w/w of a pH 9.5-10.5 buffer.

In some embodiments, the formulations of this invention comprise from about 0.1 % to 2% w/w of the compound of formula I, II, Ia, lla, Ia^*, or Ha^*; from about 50% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 7% to 9% w/w of one or more emollients; from about 10.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.2% of one or more antioxidants; and from about 20% to 28% w/w of a pH 9.5-10.5 buffer.

In some embodiments, the formulations of this invention comprise from about 0.1 -1.0% of the compound of formula I, II, Ia, lla, Ia*, or lla^*,; from about 45% to 55% petrolatum; from about 6% to 10% mineral oil; from about 3% to 8% polyoxyl stearyl ether; from about 0.01 % to 0.1 % butylated hydroxyanisole; and from about 20% to 28% w/w borate buffer with a pH about 10. In some embodiments, this invention describes a method of preventing excessive scarring comprising the topical administration of a formulation of this invention, wherein said administration is to a mammal's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.

In some embodiments, this invention describes a method of preventing excessive scarring comprising the topical administration of a formulation of this invention, wherein said administration is to a human's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.

In some embodiments, the methods of his invention comprise the repeated administration of a topical formula of this invention.

In some embodiments, the excessive scarring to be prevented is hypertrophic. For purposes of this invention, definitions as they apply to the structural formulae descriptors are as follows: C-\ .4 alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C-μβalkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Cn-4alkyl and Co-6^alM additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).

C₂.₆alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C_2-5 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.

C₂.₆alkynyl means an alkyl; group of 2 to 6 carbons wherein one carbon- carbon single bond is replaced by a carbon-carbon triple bond. C₂.6alkynyl includes acetylene, 1 -propyne, 2-propyne, 1 -butyne, 2-butyne, 3-butyne and the isomers of pentyne and hexyne.

Ci.₄oxoalkyl refers to an alkyl group of up to four carbons wherein a CH₂ group is replaced by a C(O), or carbonyl group. Substituted formyl, acetyl, 1- propanal, 2-propanone, 3-propanal, 2-butanone, 3-butanone, 1- and 4-butanal groups are representative. d.₆oxoalkyl includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group. C₃.β oxoalkenyl and C₃-₆ oxoalkynyl refers to a C₃.₆ alkenyl or C₃.₆alkynyl wherein a CH₂ group is replaced by a C(O) group. C₃.₄ oxoalkenyl includes 1 -oxo-2-propenyl, 3-oxo-1- propenyl, 2-oxo-3-butenyl and the like.

Any C-| _4alkyl or C-^ .Q alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 oxoalkyl, C-\ .Q oxoalkyl, C_3-4 oxoalkenyl, C3-6 oxoalkenyl and C₃.₆oxoalkynyl may be optionally substituted with the group R^x, which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques. Suitable groups for R^x are C-_j^alkyl, OR¹, SR", C-^alkylsulfonyl, C-j ^alkylsulfoxyl, -CN,

N(R')2, CH₂N(R')2, -NO₂, -CF₃, -CO₂R" -CON(R')₂, -COR', -NR¹C(O)R¹, F, Cl, Br, I, or CF3S(O)_r,wherein r is 0, 1 or 2. R14*-CI -6 alkyl refers to a Ci -6 alkyl group wherein in any position a carbon- hydrogen bond is replaced by a carbon-Ri4^* bond. Ri4^*-C2-6 alkenyl and R14^*-C₂- 6 alkynyl have a similar meaning with respect to C2-6 alkenyl and C2-6 alkynyl. Halogen or halo means F, Cl, Br, and I.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially C^alkyl, C-^alkoxy, C^alkylthio, CF₃, NH2, OH, F, Cl, Br or I.

Het, or heterocycle, indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Illustrative heterocycles are benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by chemical synthesis and are stable are within the scope of this invention.

C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds. Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention. As used herein ^ indicates a nitrogen heterocycle, which may be a saturated or unsaturated stable five-, six- or seven-membered monocyclic ring, or a seven- to ten-membered bicyclic ring containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure. The nitrogen atom in such ring may be substituted so as to result in a quaternary nitrogen. The nitrogen heterocycle may be substituted in any stable position by H, Ci-4alkoxy, F,

Cl, Br, I, NO2, N(R'^*)2, OH, CO2R'^*, CONHR^1*, CF3, Ri4^*-C_υ-4alkyl, R14^*-CI - 4alkyl-S(O)_u* (e.g., where u^* is 0, 1 or 2) or Ci-4alkyl substituted by any of the

aforementioned substituents. Representative of ^ are pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyraxolidine, piperidine, piperazine, morpholine, pyridine, pyridinium, tetrahydropyridine,tetrahydro- and hexahydro-azepine, quinuclidine, quinuclidinium, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. In particular, ^ may be pyridyl, pyrolidinyl, piperidinyl, piperazinyl, azetidinyl, quinuclidinyl or tetrahydropyridinyl. ^ is preferably 4-pyridyl, 4-(2-amino-pyridyl), 4-tetrahydropyridyl, 4-piperidinyl or 4- piperazinyl.

When Rb and R^c are joined together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which R^ and R^c are attached, the ring formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring. Preferably R_j3 and R_c will be -D1=D2-D3=D4 wherein D1 - D4 are independently CH, N or C-R_x with the proviso that no more than two of D1 - D4 are N. Most preferably, when R^ and R^c are joined together they form the group -CH=CH-CH=CH-.

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refers to the benzyl radical, Me refers to methyl, Et refers to ethyl, Ac refers to acetyl, AIk refers to C^ _4alkyl, Nph refers to 1 - or

2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.

The preparation of the compounds of this invention are described in WO 98/14192 and US 6,495,560. This invention describes methods of using vitronectin receptor antagonists for the prevention of scarring and can be administered via any method deemed appropriate to accomplish that purpose. It is preferred that the methods of this invention utilize a topical administration of a vitronectin receptor antagonist. The methods of this invention may be used to treat or prevent scarring or excess scar formation. By prevention of excess scarring, it is meant that the methods of this invention are preferably utilized before a scar has healed entirely. Some non-limiting examples of vitronectin receptor antagonists useful for the purposes of this invention are described in include those described in the following: PCT Application No. PCT/US95/08306, published as WO 96/00730; PCT Application No. PCT/US95/08146, published as WO 96/00574; PCT Application No. PCT/US96/11108, published as WO97/01540; PCT Application No. PCT/US96/20748, published as WO 97/24119; PCT Application No. PCT/US96/20744, published as WO WO97/24122; PCT Application No. PCT/US96/20327, published as WO 97/24124; PCT Application

No.PCT/US98/00490, published as WO 98/30542; PCT Application No. PCT/US98/19466, published as WO 99/15508; PCT Application No. PCT/US99/28622, published as WO 00/33838, which are herein incorporated by reference. In some aspects, this invention provides a formulation comprising a compound of formula I, II, Ia, Ha, Ia^*, or Ha* which is suitable for topical administration. In some embodiments, the compound of formula I, II, Ia, Ha, Ia*, or Ha^* is present in from about 0.01 % to 99% w/w of the formulation, or from about 0.01% to 50%, or from about 0.01 to 10%, or from about 0.05% to 5%, or from about 0.1 % to 2%, or from about 0.1 % to 1 %, or about 2%, or about 1 %, or about 0.5%, or about 0.1 %.

In certain embodiments, this invention describes a compound of formula I, II, Ia, Ha, Ia^*, or Ha* which is suitable for topical administration wherein said formulation includes at least one penetration enhancer. For purposes of this invention, a penetration enhancer is any substance which facilitates the absorption of a substance through the skin and for purposes of this invention, water is excluded from the definition of a penetration enhancer. Also to be excluded from the definition of a penetration enhancer is any substance whose primary purpose is as a wax, ointment, base or emollient. Penetration enhancers may sometimes serve as drug substance solubilizers. Among the classes of compounds useful as penetration enhancers are low molecular weight alcohols such as methanol, ethanol, 2-propanol, propylene glycol, and the like. Higher molecular weight alcohols may also be sometimes used, such as polyethylene glycols (PEG), and the like. Alkyl methyl sulfoxides such as dimethyl sulfoxide (DMSO), decylmethyl sulfoxide or tetradecylmethyl sulfoxide and the like, may also be useful. Pyrrolidinones such as 2-pyrrolidinone, N-methyl-2- pyrrolidinone or N-(2-Hydroxyethyl)pyrrolidone, and the like, might also be useful. Laurocapram might also be useful as well as additional miscellaneous solvents such as acetone, dimethyl acetamide, dimethyl formamide, glycol ethers (such as diethylene glycol monomethyl ether (Transcutol^®), caprylocaproyl macrogol-8 glycerides (Labrasol^®), or tetrahydrofurfuryl alcohol, and the like, might also be useful for the formulations and methods of this invention. Surfactants might also serve as penetration enhancers. Surfactants include amphiphilic molecules such as anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants (such as polyoxyethylene alkyl ethers including macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers) and fatty acids or alcohols (such as benzyl alcohol). The penetration enhancer or enhancers may be present in any amount deemed to be effective for the particular formulation and indication being studied. In some embodiments, the penetration enhancer or enhancers is present in from .5% to 99%, in some embodiments .5% to 40%, in some embodiments .5% to 25%, in some embodiments 1% to 25%, in some embodiments 4% to 18%, in some embodiments 10% to 18%, in some embodiments 10%, or 11%, or 12%, or 13%, or 14%, or 15%, or 16%.

In some embodiments, the formulations of this invention include one or more waxes, ointments, or bases, or a combination thereof. In the broader sense, ointments, bases or waxes of this invention typically include semisolid substances which serve as vehicles for the delivery of the drug substance while not undergoing significant absorption itself. Ideally, these substances are compatible with the skin, possess good stability, are smooth and readily applied (pliable), are not irritating or sensitizing, and are capable of delivering the drug substance. Substances serving as waxes, oils, or ointments in this invention are preferably not highly absorbed by the skin. Useful bases include petrolatums such as white petroleum jelly, yellow petroleum jelly, polyethylene glycol, and mineral jelly, and the like. In some embodiments, the wax, ointment, or base, or combination thereof, is present in from 0.5% to 99%, in some embodiments from 25% to 75%, in some embodiments from 40% to 60%, in some embodiments from 50% to 60%, in some embodiments 45% to 55%, in some embodiments about 50%, or about 51 %, or about 52%, or about 53%, or about 54%, or about 55%, or about 56%, or about 57%, or about 58%.

In certain embodiments, the formulations of this invention, and methods of treatment using the formulations of this invention include a pH-buffered solution. In some embodiments, the pH-buffered solution is present in from about 0.5% to 65% w/w of the formulation, in some embodiments from about 1 % to 45% w/w; or from about 5% to 35% w/w; or from about 10% to 30% w/w; or from about 20% to 28% w/w; or about 24%. The pH buffer of this invention facilitates the transport of the compounds of this invention, especially where said compounds are capable of forming zwitterionic salts. In the case where a compound of this invention can form a zwiterrionic salt, the buffer can serve to facilitate the deprotonation of said salt and thus reduce the zwitterionic character of the drug substance. The pH of the buffer selected as well as the chemical make up of the buffer are to be determined primarily by the contents of the formulation, including the drug used in the formulation. In certain embodiments, the buffers used in the formulations of this invention have a pH of about 8 to 11 ; or about 9 to 11 ; or about 9.5 to 10.5; or about 9.6 to 10.4, or about 10. In some embodiments, the pH buffers of this invention consist of a weak acid and its conjugate base. Some non-limiting examples of buffers of this invention include (H₃BO₃Z[B(OH)₄]^"); (HCO₃VCO₃ ²-); (HSO₄VSO₄ ²-); (H₂PO₄V HPO₄ ^2"); citrate/citric acid; and tartrate/tartaric acid.

The pH of the topical formulations of this invention may be controlled by the inclusion of an acid or base buffer, or a pharmaceutically acceptable acid or base in a non-buffered embodiment. In this non-buffered context, the base or acid used maybe organic or inorganic. In certain embodiments, the formulations of this invention have pHs of >7, or >8, or about from 8.5 to about 9.5, or from about 8 to about 9, or from about 7.5 to 8.5, or from about 7 to about 9, or from about 8.5 to 8.7. In certain embodiments, it is advantageous to utilize formulations that have their pHs controlled primarily with a pharmaceutically acceptable acid. Such acids can be used to bring the pH down into a desired range of less than 7, or less than 6, or from about 5 to 7, or from about 4 to 6, or from about 3 to 6, or about 4.

In some embodiments, the formulations of this invention include one or more emollients. Emollients are typically bland, fatty or oleaginous substances which helps to both soften the skin as well as protect the skin from various air born contaminants while the skin heals. Some non-limiting examples of emollients useful for the purposes of this invention include cetostearyl alcohol, sesame oil, lanolin, mineral oil, coconut oil, sulfated castor oil, petrolatum, corn oil, isopropyl palmitate, cetyl esters wax, lecithin, cholesterol, glycerol, glyceryl monostearate, castor oil, isopropyl myristate, mineral oil, petrolatum (white or yellow), petrolatum alcohols, cold cream, cotton seed oil, hydrophilic ointment, rose water ointment, and theobroma oil. The emollient or emollients, if used, may be present in any amount deemed beneficial to the particular formulation contemplated. For example, an emollient or emollients maybe present in from about 0.1 % to 65% w/w of the formulation, or from about 0.5% to 45%, or from about 2% to 25%, or from about 4% to 15%, or from about 4% to 12%, or from about 6% to 10%, or from about 7% to 9%, or from about 6%, or about 7%, or about 8%, or about 9% or about 10%. In some embodiments, the formulations of this invention include one or more antioxidants. For purposes of this invention, an antioxidant is any substance that can prevent, hinder, slow or otherwise inhibit the oxidative deterioration of any component of the formulation. Some non-limiting examples of antioxidants contemplated for use in this invention include ascorbic acid, ascorbic acid esters, butylated hydroxyanisole, butylated hydroxytoluene, sodium or potassium metabisulfite, sodium or potassium bisulfite, fumaric acid, malic acid, alpha tocopherol, or propyl gallate. In some embodiments, the formulations of this invention contain from about 0.001% to 5% antioxidant, or from about 0.001% to 4%, or from about 0.001 % to 3%, or from about 0.001 % to 2%, or from about 0.01 % to 1 %, or from about 0.01 % to 0.5%, or from about 0.01 % to 0.4%, or from about 0.01 % to 0.3%, or from 0.01 % to 0.2%; or from about 0.1 % to 1%, or from about 0.1 % to 0.5%, or from about 0.1% to 0.4%, or from about 0.1% to 0.3%, or from about 0.1% to 0.2%, or about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%, or about 0.5%. In some embodiments, the formulations of this invention may include an antimicrobial agent. Some non-limiting examples of antimicrobial agents contemplated for the purposes of this invention are benzoic acids or benzoate salts, editic acid, phenol, sorbic acid, benzyl alcohol, isopropyl alcohol, benzethonium chloride, propylparaben, imidurea, propionate salts, bronopol, butylparaben, cetrimide, chlorhexidine, phenylmercuric nitrate, potassium sorbate, propylene glycol, chlorbutanol, chlorocresol, cresol, ethylparaben, glycerol, methylparaben, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, and thimersol.

It is to be understood that formulations of this invention are comprised of various possible combinations of those ingredients or excipients listed above. Accordingly, formulations may comprise combinations of those ingredients in the described ranges or the formulation may comprise subcombinations of ingredients or excipients listed above wherein not every category of excipient or ingredient is represented in every formulation.

Furthermore, it is to be understood that any of the methods of this invention maybe combined with any of the formulation embodiments of this invention and that this invention is not limited to the specifically enumerated embodiments. Typical Formulations Table 1

Table 7

Table 8

Ingredients Ranges

Compound of Formula I or Il 0.05% to 5% w/w

Wax(es)/Ointment(s)/Base(s) 40% to 60%

Emollient(s) 6% to 10%

Penetration Enhancer(s) 1 % to 25%

Antioxidant(s) 0.01 % to 1 %

Buffer(s) 5 - 35% (pH 9-11)

Additional Ingredients qs to 100%

Table 9

Ingredients Ranges

Compound of Formula I or Il 0.1% to 2% w/w

Wax(es)/Ointment(s)/Base(s) 40% to 60%

Emollient(s) 6% to 10%

Penetration Enhancer(s) 4% to 18%

Antioxidant(s) 0.01% to 0.5%

Buffer(s) 10 - 30% (pH 9.5-10.5)

Additional Ingredients qs to 100%

Table 10

Ingredients Ranges

Compound of Formula I or II 0.1 % to 1 % w/w

Wax(es)/Ointment(s)/Base(s) 50% to 60%

Emollient(s) 7% to 9%

Penetration Enhancer(s) 10% to 18%

Antioxidant(s) 0.01% to 0.2%

Buffer(s) 20 - 28% (pH 9.6-10.4)

Additional Ingredients qs to 100%

Table 11

Ingredients Ranges

Compound Ia^* or Ha^* 0.01% to 10% w/w

Wax(es)/Ointment(s)/Base(s) 25% to 75%

Emollient(s) 4% to 12%

Penetration Enhancer(s) 0.5% to 40%

Antioxidant(s) 0.001% to 2%

Buffer(s) 1 - 45% (pH 8-11)

Additional Ingredients qs to 100% Table 12

Ingredients Ranges

Compound Ia* or Ha* 0.05% to 5% w/w

Wax(es)/Ointment(s)/Base(s) 40% to 60%

Emollient(s) 6% to 10%

Penetration Enhancer(s) 1% to 25%

Antioxidant(s) 0.01 % to 1%

Buffer(s) 5 - 35% (pH 9-11)

Additional Ingredients qs to 100%

Table 13

Ingredients Ranges

Compound Ia* or Na* 0.1% to 2% w/w

Wax(es)/Ointment(s)/Base(s) 40% to 60%

Emollient(s) 6% to 10%

Penetration Enhancer(s) 4% to 18%

Antioxidant(s) 0.01% to 0.5%

Buffer(s) 10 - 30% (pH 9.5-10.5)

Additional Ingredients qs to 100%

Table 14

Ingredients Ranges

Compound Ia^* or Ha^* 0.1 % to 1 % w/w

Wax(es)/Ointment(s)/Base(s) 50% to 60%

Emollient(s) 7% to 9%

Penetration Enhancer(s) 10% to 18%

Antioxidant(s) 0.01% to 0.2%

Buffer(s) 20 - 28% (pH 9.6-10.4)

Additional Ingredients qs to 100%

EXAMPLES

Table 15 Example Formulation 1 (cream)

Table 16 Example Formulation 2 (cream)

Table 17 Example Formulation 3 (cream)

Table 18 Example Formulation 4 (ointment)

Table 19 Example Formulation 5 (ointment)

Table 20 Example Formulation 6 (cream)

Table 21 Example Formulation 7 (gel)

Table 22 Example Formulation 8 (gel)

Ingredients Ranges

Compound Ia* 1.0%

Carbopol 934P 1.0%

Transcutol 50%

Purified water 48%

Table 23 Example Formulation 9 (solution)

Ingredients Ranges

Compound Ia* 2.0%

Transcutol 98%

Table 24 Example Formulation 10 (solution)

The methods of this invention are directed to the administration of vitronectin receptor antagonists which are useful for the prevention of excessive scarring of skin. In some embodiments, the formulations of this invention are useful for the treatment of normal, hypertrophic or keloid scarring. In some embodiments, the formulations of this invention maybe used to prevent hypertrophic or normal scarring. In some embodiments, the formulations of this invention maybe used as a method of treating hypertrophic scarring. The methods of this invention relate to the prevention of scarring of the skin which occurs after an injury or insult to the skin, most often in the form of a cut or splitting in the skin which upon healing, might form a normal scar, a hypertrophic scar or a keloid scar. The treatment methods of this invention comprise the administration of a vitronectin receptor antagonist, wherein said administration may be oral, parenteral, inhaled, topically, or through a mucous membrane via insert or suppository. The compositions of vitronectin receptor antagonists useful for the purposes of this invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. Liquid formulations useful for the methods of this invention may be buffered or non-buffered. Some examples of suitable diluents are normal isotonic saline solutions, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. While such formulations are especially suitable for parenteral administration, they may also be used in oral administrations, or contained in a metered dose inhaler or a nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, mannitol, sodium chloride or sodium citrate.

Alternatively, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier may vary according to the need, but typically will include between 10 mg and 750 mg per dosage unit. These pharmaceutical preparations can be made according to conventional techniques such as milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. If a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled in a soft gelatin capsule.

Rectal or vaginal administration may also be used to perform the methods of this invention and accordingly, vitronectin receptor antagonists may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded or formed into a suppository.

When a vitronectin receptor antagonist is administered orally, the typical dosage will be between 0.1 mg/kg and 50 mg/kg, depending upon the particular antagonist used as well as the particulars of the patient's condition and presentation. Preferably, the oral dosage will be between 0.5 mg/kg and 25 mg/kg. For acute administration, an intravenous infusion of the vitronectin receptor antagonist in an aqueous solution may be preferable. For these purposes, the vitronectin receptor antagonist may be conveniently coadministered, if desired, with other substances via the IV. Typically, a dose via IV will be between 0.1 mg/kg and 20 mg/kg and may be administered as needed. Alternatively, the vitronectin receptor antagonist may be administered via a depot formulation wherein the substance is injected or placed into a subdermal depot and allowed to release over a period of time. Vitronectin receptor antagonists may also be injected intradermally which is accomplished by injection of a vitronectin antagonist near the wound site. The injections may be administered once or as part of a series of injections depending on what the situation dictates. In some embodiments, this invention describes the topical application of a vitronectin receptor antagonist to injured skin in order to prevent excess scarring. In some embodiments, the formulation of this invention may be topically applied once and in some embodiments, the formulation will need to be applied repeatedly. By repeated applications, it is meant that the formulation will be applied and then after a period of time, another application will be made, and so on until the desired level of benefit is achieved. The treatment regimen maybe comprised of formulations of this invention administered prior to, or coadministered or administered subsequently to therapy with other known or possible scar formation palliatives including surgery, pressure, corticosteroids, radiation, silicone, laser, cryotherapy, formalin, pepsin, HCI, oil of creosote, penacillamine, colchicines, 5-fluorouracil, bleomycin and interferon.

The formulations of this invention may be administered in any form suitable for a topical administration. A formulation of this invention may be prepared as, and administered, for example, a cream, ointment, solution, gel, salve, emulsion, lotion, suspension or a semi-solid. The methods and formulations of this invention may also be administered with a wound healing device. For example, a bandage, wrap, cast and the like, may be impregnated with a vitronectin receptor antagonist and be placed over the wound site, and the device changed as needed. Cream formulations are generally prepared using an emulsification process whereby the aqueous and oil phases are first prepared in separate vessels. Temperatures of both phases are maintained at high temperatures, and while hot, one phase is added to another while mixing using a high shear mixer. The final emulsion is allowed to cool, while the agitation continues at lower speeds. The cream can then be dispensed from the manufacturing vessel and filled into the primary pack, such as, for example, a tube or sachet.

The cream formulations of Example formulation #1 (Table 15), #2 (Table 16), or #3 (Table 17) in this invention were manufactured by first preparing the aqueous phase. The surfactant and buffer solution were mixed, and the appropriate amount of drug was weighed and added to the aqueous solution while stirring with a low shear propeller mixer. The temperature of the aqueous solution was maintained at 55-65°C. Concurrently, all of the components of the oil phase were added into a separate container and heated to 75-85⁰C to melt and mix the components.

The aqueous phase was then added into the oil phase while maintaining the temperature above 70⁰C and mixing with a high shear homogenizer for a minimum of 15 minutes. The emulsification process is best carried out in a conventional topical manufacturing equipment such as a Lee Kettle or Malt-Mat which allows for scraping of the materials from the sides of the vessel while the phases are being emulsified. Following the emulsification time of 15 minutes, the product was cooled to 30⁰C. During this cooling time, the homogenizer speed was reduced and low agitation was used. After the product cooled, and the cream was produced, it can then be dispensed from the manufacturing vessel into holding containers. It can then be packed into tubes or sachets as necessary.

Additionally, as the product will be used for open wounds, it may be packed using blow-fill-seal (BFS) packaging technology, where the BFS tubes may be designed in such a way that it allows for ease of use across patient and hospital settings, allows for easy application and spreading onto the wound site, and maintains sterility of the product. This offers an advantage of less painful application than that of a cream. As a further packaging option for this product and its variations, the product may be formulated with lower viscosity and packaged into spray bottles, so that the product can be easily sprayed and applied to the wound site. This spraying provides an easier means to ensure complete coverage of the wound site without further contamination by the patient.

To manufacture a product with low bio-burden (ie aseptic conditions), both the aqueous and oil phases may be filtered through a filter, for example, a 0.22 μm filter which removes all possible organisms, including spore-forming organisms.

For example, the aqueous phase may be first filtered though a PALL cartridge filter (Pall Corporation, East Hill, NY, USA, 11548) which is contained in a heated filter housing directly into the manufacturing vessel. Thereafter, the oil phase is filtered through the same filter and filter housing, under positive pressure (20-30 psi, specifically 25 psi), thereby allowing for any remaining aqueous phase (containing drug) to also be carried into the manufacturing vessel. This minimizes active drug loss. As the oil phase is added into the already filtered aqueous phase, this manufacturing process uses phase inversion to manufacture the final water-in-oil cream. Once both phases have been filtered into the manufacturing vessel, the emulsion is manufactured by continuing to homogenize and agitate at high temperatures for a specified time period (10-20 mins, spec 15 min). Following the homogenization period, as previously described, the product is cooled while mixing, and then packaged after the final emulsion is formed. The formulations of this invention may be evaluated to determine their ability to provide reasonable percutaneous flux through human skin. Although the compounds and formulations for the topical administration according to the methods of this invention are to be used primarily for a localized action (e.g. prevention and treatment of scars), for which penetration across the skin is not necessary, in vitro human skin penetration assays are used as a surrogate to determine effectiveness of formulations. Positive results in these human skin penetration assays, which indicate permeation through the skin, suggests that drug will deposit within the skin layers, the target for pharmacological action.

For purposes of preformulation of compounds of this invention, it is useful to first determine the solubility of the vitronectin receptor antagonist in question. The physicochemical properties of a compound of formula Ia^* render it to be a difficult to deliver molecule across the skin, since typically molecules should have a MW less than 300, and log D of ~ 2 at physiological pH, and should have a reasonable solubility in aqueous and lipoidal phases, to allow for optimal delivery in the skin layers. For example, the solubility of compound Ia in water is pH dependent as shown in Table 25. Consistent with the zwitterionic nature of compound Ia*, solubility was higher at the extreme ranges of the values tested and decreased as the pH became more neutral. Within the tested range, solubility was highest at pH 8 reaching close to 5 mg/mL The solubility of the compound in typical dermatological solvents was also tested as shown in Table 26. These results indicate that despite its zwitterionic nature, the compound of formula Ia^* solubility may be improved in a dermatological formulation through appropriate use of co-solvents.

Table 25 pH-Solubility Profile of Compound of Formula Ia*

As a result of the low aqueous solubility of the compound of formula Ia*, it was critical to improve its solubility profile in the formulation. A number of solvents were evaluated to enhance the amount of Ia^* that could be delivered in solution. Some penetration enhancers tested include propylene glycol, polyethylene glycol, ethylene diglycol, polysorbate 80, amongst others.

Table 26 Solubilit of Com ound of Formula Ia* in Select Solvents for To ical Formulation^1'

Single determination using a visual solubility method ¹Trade name for "caprylocaproyl macrogolglycerides"

Two important parameters for defining optimal delivery of molecules across the skin include: (a) amount of drug in solution in the formulation; and (b) use of penetration enhancers to improve delivery.

In selecting solubility or penetration enhancers, the following factors need to be kept in mind:

(a) safety and tolerability of the agent

(b) non-irritancy

(c) no pharmacological effect of its own

(d) compatibility with the active pharmaceutical ingredient (e) regulatory acceptance (GRAS-listed or on the Inactive Ingredients list)

(f) effectiveness of the agent in either increasing solubility or penetration

Note, that in the choice of these agents, it is possible that one may function both as a solubilizer as well as a penetration enhancer.

Table 27 lists some formulations that were prepared for flux studies. Formulations prepared for the compound of formula Ia^* used GRAS-listed excipients. Formulations were adapted to ensure that all drug is in solution in its respective phase. For this study, the drug concentration was capped at 1 % and 2%. A series of solubility screening studies were completed prior to the formulation stage to determine the concentration of the compound of formula Ia^* that could be dissolved in pure solvent, as well as in solvent: water systems. PEG200, propylene glycol, benzyl alcohol and transcutol afforded the good solubility, and hence were used in the formulations. Each of the formulations also included the use of known penetration enhancers.

Table 27

Formulations of Compound of Formula Ia* Prepared for First Skin Flux

Studies

Each of these formulations was studied in an in vitro skin flux experiment. Briefly, abraded dermatomed human abdominal skin was placed across two static Franz diffusion cells. The skin was tape-stripped to reflect the wound indication. Formulation was placed in the "donor" cell, and samples taken from the "receptor" cell at predetermined time intervals over a 24-hour period. Samples were analyzed using an LC-MS-MS method, and flux (permeation rate) calculated over 24 hours. The resulting data is shown in Figure 1. The flux of the compound of formula Ia^* ranged from below the level of quantitation to 2.77 ng/(cm^2*hr) from 0-4 hours exposure, 0.18 to 4.28 ng/(cm^2*hr) from 4-24 hours exposure, and 0.19 to 4.37 ng/(cm²*hr) from 0-24 hours exposure. The highest drug flux over 24 hours was observed from the dual enhancer cream on the abraded skin (4.37 ng/(cm²*hr)). The ointment formulation produced the next largest flux rate (0.58 ng/(cm^2*hr)). The hydrophilic ointment produced comparable flux rates on both the intact skin and the abraded skin (0.19 ng/(cm²*hr) and 0.21 ng/(cm^2*hr), respectively). The cumulative percent of the applied dose of the compound of formula Ia^* penetrating the skin over the 24 hour duration of exposure ranged from 0.009% to 0.223%. The highest percent of applied dose penetrating the skin was observed with the dual enhancer cream on the abraded skin, 0.223%.

Based on the promising results of the first skin flux studies, additional formulations were prepared to further optimize the delivery of the compound of formula Ia* and the results are summarized in Table 28.

Table 28 lists some formulations exemplified in this invention together with flux data. The protocol for conducting the in vitro skin flux is briefly as follows. Abraded dermatomed human abdominal skin was placed across two Franz diffusion cells. The skin was tape-stripped to reflect the wound indication. The formulation was placed in the donor cell, and samples were taken from the receptor cell at predetermined time intervals over a 24-hour period. Samples were analyzed using an LC-MS-MS method, and flux (permeation rate) calculated over 24 hours.

Table 28

Percutaneous Flux Through Human Skin of Compound Ia^* Topical Formulations

* PG: Propylene Glycol; PEG200: polyethylene glycol

Target Flux: Intact Skin: 200 ng/cm²/hr; Dermis alone (or abraded): 1000 ng/cm²/hr

The foregoing examples and information has been provided to illustrate the invention, not limit it. What is reserved to the inventors is to be measured by the claims hereinafter.

Claims

What is claimed is:

1. A method of inhibiting excess scar formation on skin comprising the administration of a vitronectin receptor antagonist in a pharmaceutically acceptable formulation to a mammal in need thereof.

2. The method of claim 1 wherein said mammal is a human.

3. The method of claim 1 or 2, wherein said administration is topical.

4. The method of claims 1 , 2, or 3, wherein the vitronectin receptor antagonist comprises a compound of formula I or II:

wherein:

R is H, C-_I-6 alkyl, Ar, Het, or C_1-6alkylaryl;

R is R , A-Co-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4oxoalkenyl, A-C3-4θxoalkynyl, A-C-] _4aminoalkyl, A-C3_4aminoalkenyl, or A-C3_4aminoalkynyl, unsubstituted or substituted by any accessible combination of one or more of R^{1 0} or

R⁷;

A is H₁ C3-6cycloalkyl, Het or Ar;

R⁷ is -COR⁸, -COCR'2R⁹, -C(S)R⁸, -S(O)_mOR', -S(O)_mNR'R", -PO(OR¹), -PO(OR')2, -NO2, or tetrazolyl; each R8 is independently -OR¹, -NR¹R", -NR'SO2R\ -NR¹OR¹, or -OCR'2CO(O)R';

R⁹ is -OR¹, -CN, -S(O)₁-R¹, -S(0)_mN(R')2, -C(O)R¹, C(0)N(R')2. or -CO2R¹; R¹⁰ is H, halo, -OR^{1 1} , -CN, -NR¹R^{1 1} , -NO2, -CF₃, CF₃S(O)_n -CO2R¹, -C0N(R')2, A-Co-6alkyl-ι A-Ci -βoxoalkyl-, A-C2-6alkenyI-, A-C2-6alkynyl-, A-Crj-βalkyloxy-, A-Cn-βalkylamino- or A-Crj-6alkyl-S(O)r;

R^{1 1} is R¹, -C(O)R¹, -C(O)N(R')2, -C(O)OR¹, -S(O)_mR\ or -S(0)_mN(R')2;

W is -(CHRg)_a-U-(CHRg)b-;

U is absent or is CO, CRS₂, CC=CRQ₂), S(OJi₀ O, NR9, CR9OR9, CR9(OR^k)CRg₂, CR9₂CR9(OR^k), C(O)CR9₂, CR9₂C(O), CONR", NR'CO, OC(O), C(O)O₁ C(S)O, OC(S), C(S)NRQ, NR9C(S), S(O)₂NRg, NRgS(O)₂ N-N, NRgNRg, NR9CR9₂, CR9₂NRg, CR9₂O, OCR9₂, C≡C or CRg=CRS;

G is NR^e, S or 0;

Rg is H, C-μgalkyl, Cs-ycycloalkyl-Co-βalkyl or Ar-Co-βalkyl; R^k is R9, -C(O)R9, or -C(O)OR^f; R' is is H, C-|_6alkyl, Het-Co_6alkyl, Cs-ycycloalkyl-Cn-ealkyl, Ar- C_υ-6alkyl, or C-| .galkyl substituted by one to three groups chosen from the group consisting of halogen, CN, NR9₂, OR9, SR9, CO₂RS, and CON(RS)₂;

R^f is H, C-μβalkyl or Ar-Cn-6alkyl; R^e is H, C-| .galkyl, Ar-Cn-βalkyl, Het-Cn-6alkyl, Cs-ycycloalkyl-Crj-ealkyl, or

(CH₂)_kCO₂Rg;

Rb and R^c are independently selected from the group consisting of H, C-| . galkyl, Ar-Cg.galkyl, Het-Cn-βalkyl, C3-6cycloalkyl-Co_6alkyl, halogen, CF3, OR^,

S(O)_kR^f, COR^f, NO₂, N(R^f)_2i CO(NRf)₂, and CH₂N(R^f)₂, or R^b and R^c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, C-^alkyl, 0R^f, S(O)_kR^f, COR^f, CO₂R^f, OH, NO₂, N(R^f)_2] C0(NR^f)₂, CH₂N(R^f)₂, and methylenedioxy;

Q¹ , Q², Q³ and Q⁴ are independently N or C-RY, provided that no more than one of Q¹ , Q², Q³ and Q⁴ is N;

R¹ is H, Ci -6alkyl, Ar-Crj-βalkyl or Cs-θcycloalkyl-Co-βalkyl;

R" is R', -C(O)R' or -C(O)OR¹;

R'" is H, C-_| .galkyl, Ar-Cn-_βalkyl, Het-Cr_j-6alkyl, Cs-Qcycloalkyl-Cn-ealkyl, halogen, CF₃, 0R^f, S(O)_kR^f, COR^f, NO₂, N(R^f)₂₎ CO(NRf)₂, or CH₂N(Rf)₂; RY is H, halo, -0R9, -SR9, -CN, -NR9R^k, -NO₂, -CF₃, CF₃S(O)_n -CO₂R9,

-C0R9 or -CONRS₂, or Ci -βalkyl unsubstituted or substituted by halo, -ORS, -SR9, - CN, -NR9R", -NO₂, -CF₃, R¹S(O)_n -CO₂R9, -COR9 or -CONR9₂; a is 0, 1 or 2; b is O, 1 or 2; k is O, 1 or 2; m is 1 or 2; r is O, 1 or 2; s is O, 1 or 2; u is O or 1 ; and v is O or 1 , or a compound of formula II;

wherein Ai is C or N;

E is a five- or six-membered heteroaromatic or six-membered aromatic ring unsubstituted or substituted by R3* or R4*;

X1-X2 is CHR1*-CH, CR1 ^*=C, NR1 ^*-CH, S(O)_U*-CH or O-CH; X3 is CR5*R5'*, NR5*, S(O)_U* or O; R¹* is H, d-e alkyl, Ar, Het, d-ealkylaryl;

R"* is R¹*, -C(O)R¹* or -C(O)OR5*; R'"^* is C-| -6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;

R1 ^* is H, Ci -6alkyl, or Ar-Crj-4alkyl; R2^* is -OR¹*, -NR'*R"*, -NR'*SO2R'"*, -NROR¹*, -OC(R'*)2C(O)OR'*, - OC(R'*)2θC(O)-R'*, -OC(R'*)2C(O)N(R'^*)2, CF3 or COC(R'^*)2R²'^*;

R2^1* is -OR^1*, -CN, -S(O)_r*R'^*, S(O)2N(R'^*)2, -C(O)R^1*, C(O)N(R'*)2 or - CO₂R¹*;

R5^* and R5¹* are independently H, C-|-6alkyl, Cs-ycycloalkyl-Co^alkyl or Ar- Cn-4alkyl; R6^* is W-(C(R'*)2)q*-Z*-(CR'*Ri 0^*)_r*-U*-(C(R'*)2)s*-V*- or W'*-(C(R¹*)2)q*-

U^*-(C(R'^*)2)s^*-;

R3*. R4* and R7* are independently H, halo, -OR12*. -SR12*. -CN₁ - NR'*R12^*, -NO2, -CF3, CF3S(O)_r*-, -CO2R^1*, -CON(R¹^₁ Ri4*-Cθ-6_a|kyl-, R14*- Ci-6oxoalkyl, Ri4*-C₂_₆alkenyl-, Ri4^*o₂-6alkynyl, Ri4^*-Co-6alkyloxy-, R14*-CQ. 6alkylamino or Ri4*-Co-6alkyl-S(0)_r*-;

R8* is R¹*, C(O)R¹*, CN, NO2, Sθ2R"^*or C(O)OR5*;

R9^* is R¹*, -CF3, -SR^1*, or -OR'*;

R1O^* is H, Ci -4alkyl or -NR'*R"*;

R12^* is R¹*, -C(O)R¹*, -C(O)N(R'*)2, -C(O)ORS^*, -S(O)_m*R'* or S(O)2N(R'*)₂; R14^* is H, C3-6cycloalkyl, Het or Ar;

R¹5^* is H, C-|-ioalkyl, Cs-ycycloalkyl-Crj-salkyl or Ar-Crj-δalkyl;

U* and V* are absent or are CO, C(R'^*)2, C=C(Ri 5^*)₂, S(O)_n*, O, NR15^*,

CR15'^*OR15^*, CR'^*(OR"^*)CR'^*2, CR'^*2CR'^*(OR"^*)_J C(O)C(R'^*)2, C(R15^*)₂C(O), CONR15^*, NR15^*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5^*, NR15^*C(S),

SO₂NR15^*, NR15^*SO₂, N=N, NR15^*NR15^*, NR15*C(R15*)_2I NR15*C(R15*)_2I

C(R15^*)₂O, OC(Ri 5^*)₂, G=C₁ CR15*_-CR15*, Het, or Ar, provided that U* and V* are not simultaneously absent;

W* is R'^*R"*N-, R'*R"^*NR'^*N-, R^R'^NR^NCO-, R'^*2NR'^*NC(=NR'^*)-, R'ONR'^*C(=NR'^*)-,

)

W* is

Q* is NR^1*, O or S; Ra^* is H, C-|-6alkyl, Ar-Co-6alkyl, Het-Co-βalM. or Cs-ecycloalkyl-Co-βalkyl, halogen, OR1^*, SR1 ^*, COR1^*, OH, N02, N(R1 ^*)2, CO(NR1^*)2, or CH2N(R1^*)2;

Rb^* and R^c* are independently selected from the group consisting of H, Ci- δalkyl, Ar-Co-6^a'W. Het-Co-βa'kyl. or C3-6cycloalkyl-Cn-6a^|kyl> halogen, OR-I^*, SR1 ^*, COR1 ^*, OH, N02, N(Ri ^*)2, CO(NRi ^*)₂, CH2N(R1 ^*)2, or Rb^* and RC^* are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci-4alkyl, OR1^*, SR1^*, COR1^*, OH, NO₂, N(R1 ^*)2, CO(NRi ^*)_2J CH2N(R1^*)2, CN, or R"^*R'^*NC(=NR'^*)-;

X* is N=CR¹, C(O) or O; Y^* is absent, S or O;

Z^* is (CH2)t*. Het, Ar or C3_7cycloalkyl;

M* is 1 or 2;

N^* is 0, 1 , 2, or 3; q^* is θ, 1 , 2, or 3; r^* is 0, 1 or 2; s^* is 0, 1 or 2; t* is 0, 1 or 2; u* is 0, 1 or 2; v^* is O or 1 ; and w* is 0 or 1 ; or or a pharmaceutically acceptable salt or solvate thereof.

5. The method of claim 4, wherein the compound of formula I is Ia

Ia

wherein R is H, Ci.₆alkyl, Ar, Het, or C_1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.

6. The method of claim 5, wherein R is H.

7. The method of claim 4, wherein the compound of formula Il is Na

Na wherein R^2* is H, d^alkyl, Ar, Het, or C_1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.

8. The method of claim 7, wherein R^2* is H.

9. The method according to any one of claims 1 through 8, wherein the excessive scarring is hypertrophic.

10. A formulation suitable for the topical administration of a compound of formula I or II,

I wherein:

R is H, Gi-salkyl, Ar, Het, C^alkylaryl

R is R , A-Co-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4θxoalkenyl, A-C3_4oxoalkynyl, A-C-_] ^aminoalkyl, A-C3_4aminoalkenyl, or A-C3_4aminoalkynyl, unsubstituted or substituted by one or more of R¹ ° or R⁷; A is H, C3-6cycloalkyl, Het or Ar;

R⁷ is -CORδ, -COCR'2R⁹, -C(S)R⁸, -S(O)_mOR', -S(O)_mNR'R", -PO(OR¹), -PO(OR')2, -NO2, or tetrazolyl; each R⁸ is independently -OR¹, -NR¹R", -NR'SCfcR¹, -NR¹OR¹, or

-OCR'2CO(O)R';

R9 is -OR', -CN₁ -S(O)₁-R¹, -S(O)_mN(R¹)2, -C(O)R', C(O)N(R¹)₂, or -CO₂R"; R1O is H, halo, -OR^{1 1} , -CN, -NR¹R^{1 1} , -NO₂, -CF3, CF3S(O)_r, -CO2R¹, -CON(R')2, A-Co-6alkyl-, A-C-|-6θxoalkyl-, A-C2-6alkenyl-, A-C₂-6alkynyl-, A-Co-6alkyloxy-, A-Crj-θalkylamino- or A-Co-6alkyl-S(0)_r;

R^{1 1} is R¹, -C(O)R¹, -C(O)N(R')2, -C(O)OR¹, -S(O)_mR\ or -S(0)_mN(R')2;

W is -(CHRg)a-U-(CHRg)b-;

U is absent or is CO, CRS₂, C(=CR9₂), S(O)I₀ O, NR9, CR9OR9, CRg(ORk)CRS₂, CRg₂CR9(OR^k), C(O)CR9₂, CRg₂C(O), CONR', NR'CO, OC(O)₁ C(O)O, C(S)O, OC(S), C(S)NRg, NR9C(S), S(O)₂NR9, NRgS(O)₂ N=N, NR9NR9, NR9CR9₂, CRg₂NRg, CR9₂O, OCRg₂, C≡C Or CRg=CRg; G is NR^e, S or O;

R9 is H, C-μgalkyl, Het-Cr_j.galkyl, C3_7cycloalkyl-Cr_j-galkyl or Ar-Crj-galkyl;

R^k is R9, -C(0)R9, or -C(O)OR^f ;

R' is is H, C-_| .galkyl, Het-Cø-galkyl, Cs-zcycloalkyl-Co-galkyl, Ar- Cr_j_galkyl, or C-_| .galkyl substituted by one to three groups chosen from the group consisting of halogen, CN, NRS₂, OR9, SR9, CO₂RS, and CON(RS)₂; R^f is H, C-j_₆alkyl or Ar-Co-6alkyl;

R^e is H, C-| .galkyl, Ar-Cn.galkyl, Het-Co-galkyl, Cs-ycycloalkyl-Crj-galkyl, or ' (CH₂)_kCO₂R9; R^D and R^c are independently selected from the group consisting of H, C-| . galkyl, Ar-Crj-galkyl, Het-Cr_j-galkyl, Cs-gcycloalkyl-Crj-galkyl, halogen, CF3, OR*,

S(O)_kR^f, COR^f, NO₂, N(R^f)_2; CO(NR^f)₂, CH₂N(R^f)₂; or R^b and R^c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, Chalky], OR^f, S(O)kR^f, C0R^f, C0₂R^f, OH, NO₂, N(R^)₂, CO(NR^f)₂, CH₂N(R^f)₂ and methylenedioxy;

Q¹ , Q², Q3 and Q^ are independently N or C-Ry, provided that no more than one of Q¹ , Q², Q³ and Q⁴ is N;

R' is H, Ci -galkyl, Ar-Crj-6alkyl or C3-gcycloalkyl-Crj-6^alkyl; R" is R¹, -C(O)R' or -C(O)OR¹;

R'" is H, C-_| .galkyl, Ar-Crj-galkyl, Het-Cr_j-galkyl, or C3-gcycloalkyl-Co-galkyl, halogen, CF₃, 0R^f, S(0)_kR^f, C0R^f, NO₂, N(R^f)_2j C0(NR^f)₂, CH₂N(R^f)₂;

Ry is H, halo, -0R9, -SR9, -CN, -NR9RI<, -NO₂, -CF₃, CF₃S(O)_Γ, -CO₂RS, -CORS or -CONRS₂, or Ci -galkyl unsubstituted or substituted by halo, -ORS, -SRS, - CN, -NRSR", -NO₂, -CF₃, R¹S(O)₁--, -CO₂R9, -CORS or -CONRS₂; a is 0, 1 or 2; b is 0, 1 or 2; k is O, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is O, 1 or 2; u is 0 or 1 ; and v is 0 or 1 ; or a compound of formula Il

wherein

Ai is C or N;

E is a five- or six-membered heteroaromatic or six-membered aromatic ring optionally substituted by R3^* or R4^*;

X1-X2 is CHR1^*-CH, CR1^*=C, NR1^*-CH, S(O)_U*-CH or O-CH; X3 is CR5^*R5'^*, NR5*, S(O)_U* or O;

R^1* is H, Ci_-6alkyl, Ar, Het, d^alkylaryl;

R"^* is R'^*, -C(O)R'^* or -C(O)ORs*; R'"^* is Cl -βalkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;

R1^* is H, Ci-6alkyl, or Ar-Co-4alkyl;

R2^* is -OR^1*, -NR'^*R"^*, -NR¹*Sθ2R'"^*, -NROR^1*, -OC(R'^*)2C(O)OR'*, - OC(R'^*)2θC(O)-R'^*, -OC(R'^*)2C(O)N(R'^*)2, CF3 or COC(R"^*)2R²'^*;

PS"^* is -OR^1*, -CN₁ -S(O)_r*R'^*, S(O)2N(R'^*)2, -C(O)R^1*, C(O)N(R'^*)2 or - CO2R^1*;

R5^* and R⁵'^* are independently H, C-| -6alkyl, C3-7cycloalkyl-Cfj-4alkyI or Ar- Co-4alkyl;

R6^* is W-(C(R'^*)2)q^*-Z^*-(CR'^*Ri 0^*)_r*-U^*-(C(R'^*)2)s*-V^*- or W'^*-(C(R'^*)2)q*" U^*-(C(R'^*)2)s^*-; R3^*, R4^* and R7^* are independently H, halo, -OR12^*, -SR12^*, -CN, -

NR-^*R12^*, -NO2, -CF3, CF3S(O)_r*-, -CO2R^1*, -CON(R^1*)2, Ri4^*-Cθ-6_a|kyl-, R14^*. C-|-6θxoalkyl. Ri4^*-C2-6alkenyl-, Ri4^*-C2-6alkynyl, Ri4^*_Co-6alkyloxy-, R14^*-C_O- βalkylamino or Ri4^*-Co-6alkyl-S(0)_r*-;

R8^* is R¹*, C(O)R¹*, CN, NO2, Sθ2R'*or C(O)OR5*; R9^* is R^1*, -CF3, -SR¹*, or -OR¹*;

R1O^* is H, Ci-4alkyl or -NR"*R"^*;

R12^* is R'^*, -C(O)R^1*, -C(O)N(R'^*)2, -C(O)OR5^*, -S(O)_m*R'^* or S(O)2N(R'^*)2;

R14^* is H, C3-6cycloalkyl, Het or Ar; R15^* is H, Cl -1 rjalkyl, Cs-ycycloalkyl-Crj-salkyl or Ar-Crj-8alkyl;

U^* and V^* are absent or CO₁ C(R'*)2, C=C(Ri 5^*)₂, S(O)_n*, O, NR15^*, CR15'^*OR15^*, CR'^*(OR"^*)CR'*2, CR'*2CR'*(OR"^*), C(0)C(R'^*)2, C(R15^*)₂C(O), CONR15^*, NR15^*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5^*, NR15^*C(S), SO2NR15^*, NR15^*SO2, N=N, NR15^*NR15^*, NR15^*C(R15^*)₂, NR15^*C(R15^*)₂, C(R15^*)₂O, OC(Ri 5^*)_2> C≡C, CR15^*=CR15^*, Het, or Ar, provided that U* and V* are not simultaneously absent;

W^* is R'^*R"^*N-, R'^*R"^*NR"^*N-, R^R'^NR^NCO-, R'*2NR'^*NC(=NR'^*)-, R¹ONR^Ct=NR^1*)-,

W* is

Q* is NR¹*, O or S;

Ra^* is H, C-i-βalkyl, Ar-Co-βalkyl, Het-Co-βalkyl, Cs-βcycloalkyl-Co-ealkyl, halogen OR1 ^*, SR1^*, COR1^*, OH₁ N02, N(R1^*)₂, CO(NRi ^*)_2i or CH₂N(Ri ^*)₂; Rb^* and Rc^* are independently selected from the group consisting of H, C-|. βalkyl, Ar-Crj-6alkyl, Het-Co-6alkyl, Cs-ecycloalkyl-Co-βalkyl, halogen, OR-I^*, SR1^*, COR1^*, OH, NO₂, N(R1^*)2, CO(NRi ^*)₂, CH₂N(Ri ^*)₂; _Or Rb^* and R^C* are joined together to form a five or six membered aromatic non-aromatic ring, unsubstituted or substituted by halogen, Ci^alkyl, OR1^*, SR1 ^*. COR1^*, OH, NO₂, N(R1^*)₂, CO(NRi ^*)₂, CH₂N(Ri ^*)₂, CN₁ or R"^*R'^*NC(=NR'^*)-;

X* is N=CR¹, C(O) or O;

Y* is absent, S or O;

Z^* is (CH₂)t*, Het, Ar or C3-7cycloalkyl;

M* is 1 or 2; N* is O, 1 , 2, or 3; q^* is θ, 1, 2, or 3; r* is 0, 1 or 2; s* is O₁ 1 or 2; t^* is O, 1 or 2; u* is O, 1 or 2; v* is O or 1 ; and w* is O or 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein: the formulation comprises from about 0.01 % to 50% w/w of the compound of formula I or Il and from about 0.5% to 99% of one or more penetration enhancers.

11. The formulation of claim 10, wherein said compound of formula I is Ia,

Ia

wherein R is H, C_1-Balkyl, Ar, Het, or (^alkylaty!; or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Ha,

Ha wherein R^2* is H₁ C_1-6alkyl, Ar, Het, of Ci-₆alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.

12. The formulation of claim 11 , wherein R and R^2* are each hydrogen.

13. The formulation according to any one of claims 10 through 12, wherein the compound of formula I, II, Ia₁ or Na, comprises from about 0.01% to 10% w/w of the formulation.

14. The formulation according to any one of claims 10 through 13, wherein the one or more penetration enhancers is present in from about 0.5% to 40% w/w of the formulation.

15. The formulation according to any one of claims 10 through 14, wherein said one or more penetration enhancers is selected from the group consisting of propylene glycol, benzyl alcohol, polyethylene glycols, dimethyl isorbide, diethylene glycol monomethyl ether, macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers, laurocapram, and caprylocaproyl macrogol-8 glycerides, or combinations thereof.

16. The formulation according to claim 15, wherein said one or more penetration enhancers comprises propylene glycol.

17. The formulation according to any one of claims 10 through 15, wherein said one or more penetration enhancers comprises at least one surfactant.

18. The formulation according to any one of claims 10 through 17, wherein said formulation has a pH of greater than about 7.

19. The formulation of claim 18, wherein said formulation has a pH of greater than 8.

20. The formulation of claim 19, wherein said formulation has a pH of from about 8.5 to 9.5.

21. The formulation according to any one of claims 10 through 19, further comprising from about 1 % to 45% w/w of a buffer having a pH in the range of from 8 to 11.

22. The formulation according to any one of claims 10 through 21 , further comprising from about 25% to 75% w/w of one or more waxes, ointments, or bases, or combinations thereof.

23. The formulation according to any one of claims 10 through 22, further comprising from about 4% to 12% w/w of one or more emollients.

24. The formulation according to any one of claims 10 through 23, further comprising from about 0.5% to 10% w/w of one or more surfactants.

25. The formulation according to any one of claims 10 through 24, further comprising from about 0.001 % to 2% of one or more antioxidants.

26. The formulation of any one of claims 10 through 12, wherein said formulation comprises: from about 0.05% to 5% of a compound of formula I, II, Ia, or Ha; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 1.0% to 25% of one or more penetration enhancers; from about 0.01% to 1% of one or more antioxidants; and from about 5% to 35% w/w of a pH 9-11 buffer.

27. The formulation of claim 26, wherein said formulation comprises: from 0.1 % to 2% w/w of the compound of formula I, II, Ia, or Ha; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 4.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.5% of one or more antioxidants; and from about 10% to 30% w/w of a pH 9.5-10.5 buffer.

28. The formulation of claim 27, wherein said formulation comprises: from about 0.1 % to 2% w/w of the compound of formula I, II, Ia, or Ha; from about 50% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 7% to 9% w/w of one or more emollients; from about 10.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.2% of one or more antioxidants; and from about 20% to 28% w/w of a pH 9.5-10.5 buffer.

29. The formulation according to claim 28, wherein said formulation comprises: from about 0.1 -1.0% of the compound of formula I, II, Ia, or Na; from about 45% to 55% petrolatum; from about 6% to 10% mineral oil; from about 3% to 8% polyoxyl stearyl ether; from about 0.01 % to 0.1% butylated hydroxyanisole; and from about 20% to 28% w/w borate buffer with a pH about 10.

30. The formulation of any one of claims 26 through 29 containing a compound of formula Ia or Ha, wherein R and R^2* are each hydrogen.

31. A method of preventing excessive scarring comprising the topical administration of a formulation of any one of claims 10 through 30, wherein said administration is to a mammal's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.

32. The method of claim 31 , wherein the mammal is a human.

33. The method of claim 31 or 32, wherein said administration comprises repeated applications.

34. The method of any one of claims 31 through 33, wherein said scarring is hypertrophic.